Novel [f-18]-labelled l-glutamic acid and l-glutamine derivatives (i), their use and processes for their preparation

ABSTRACT

What is described are the compounds and the synthesis of [F-18]-labelled L-glutamic acid, [F-18]-labelled L-glutamate, their derivatives of the formula (I) and their use.

The invention relates to the subject matter referred to in the claims,i.e. [F-18]-labelled L-glutamic acid derivatives and [F-18]-labelledL-glutamine derivatives of the general formula I, and to their use andto processes for their preparation.

The early diagnosis of malignant tumour diseases plays an important rolein the survival prognosis of a tumour patient. For this diagnosis,non-invasive diagnostic imaging methods are an important aid. In thelast years, in particular the PET (Positron Emission Tomography)technology has been found to be particularly useful. The sensitivity andspecificity of the PET technology depends essentially on thesignal-giving substance (tracer) used and on its distribution in thebody. In the hunt for suitable traces, one tries to make use of certainproperties of tumours which differentiate tumour tissue from healthysurrounding tissue. The preferred commercial isotope used for PETapplications is ¹⁸F. Owing to the short half-life of less than 2 hours,¹⁸F is particularly demanding when it comes to the preparation ofsuitable tracers. This isotope does not allow for complicated longsynthesis routes and purification procedures, since otherwise aconsiderable amount of the radioactivity of the isotope will alreadyhave faded away before the tracer can be used for diagnosis.Accordingly, it is frequently not possible to apply establishedsynthesis routes for non-radioactive fluorinations to the synthesis of¹⁸F tracers. Furthermore, the high specific activity of ¹⁸F [about 80GBq/nmol) leads to very low substance amounts of [¹⁸F]-fluoride for thetracer synthesis, which in turn requires an extreme excess of precursor,making the result of a radio synthesis strategy based on anon-radioactive fluorination reaction unpredictable.

FDG ([¹⁸F]-2-Fluorodeoxyglucose)-PET is a widely accepted and frequentlyused auxiliary in the diagnosis and further clinical monitoring oftumour disorders. Malignant tumours compete with the host organism forglucose as nutrient supply (Warburg O., Über den Stoffwechsel derCarcinomzelle [The metabolism of the carcinoma cell], Biochem.Zeitschrift 1924; 152: 309-339; Kellof G., Progress and Promise ofFOG-PET Imaging for Cancer Patient Management and Oncologic DrugDevelopment, Clin. Cancer Res. 2005; 11(8): 2785-2807). Compared to thesurrounding cells of the normal tissue, tumour cells usually have anincreased glucose metabolism. This is exploited when usingfluorodeoxyglucose (FDG), a glucose derivative which is increasinglytransported into the cells, where, however, it is metabolically capturedas FDG 6-phosphate after phosphorylation (“Warburg effect”).Accordingly, ¹⁸F-labelled FDG is an effective tracer for detectingtumour disorders in patients using the PET technology. In the hunt fornovel PET tracers, recently, amino acids have been employed increasinglyfor ¹⁸F PET imaging (for example (review): Eur. J. Nucl. Med. Mol.Imaging May 2002; 29(5): 681-90). Here, some of the ¹⁸F-labelled aminoacids are suitable for measuring the rate of protein synthesis, but mostother derivatives are suitable for measuring the direct cellular uptakein the tumour. Known ¹⁸F-labelled amino acids are derived, for example,from tyrosine amino acids, phenylalanine amino acids, praline aminoacids, asparagine amino acids and unnatural amino acids (for example J.Nucl. Med. 1991; 32: 1338-1346, J. Nucl. Med. 1996; 37: 320-325, J.Nucl. Med. 2001; 42: 752-754 and J. Nucl. Med. 1999; 40: 331-338).Glutamic acid and glutamine as ¹⁸F-labelled derivatives are not known,whereas non-radioactive fluorinated glutamine and glutamic acidderivatives are known; thus, for example, those which carry fluorine inthe γ-position (for example (review): Amino Acids Apr., 2003; 24(3):245-61) or in the β-position (for example Tetrahedron Lett. 1989;30(14): 1799-1802, J. Org. Chem. 1989; 54(2): 498-500, Tetrahedron:Asymmetry 2001; 12(9): 1303-1312).

Glutamic acid derivatives having protective groups at the chemicalfunctionalities and a leaving group in the β- or γ-position have alreadybeen reported in the past. Thus, there has been a report of glutamatehaving mesylate or bromide in the γ-position whose acid and aminefunctions were provided with ester and Z protective groups,respectively, (J. Chem. Soc. Perkin Trans. 1; 1986; 1323-1328) or, forexample, of γ-chloroglutamic acid without protective groups (Synthesis;(1973); 44-46). There have also been various reports of similarderivatives where the leaving group was located in the β-position: forexample Chem. Pharm. Bull.; 17; 5; (1969); 879-885, J. Gen. Chem. USSR(Engl. Transl.); 38; (1968); 1645-1648; Tetrahedron Lett., 27; 19;(1986); 2143-2144, Chem. Pharm. Bull.; EN; 17; 5; 1969; 873-878, PatentFR 1461184, Patent JP 13142.

The PET tracers currently used in tumour diagnosis have some undisputeddisadvantages: thus, FDG is preferably accumulated in cells having anelevated glucose metabolism; however, under different pathological andphysiological conditions, as also in elevated glucose metabolism in thecells and tissues involved, for example infection sites or wound healing(summarized in J. Nucl. Med. Technol. (2005), 33, 145-155), Frequently,it is still difficult to ascertain whether a lesion detected via FDG-PETis really of neoplastic origin or is the result of other physiologicalor pathological conditions of the tissue. Overall, the diagnosis byFDG-PET in oncology has a sensitivity of 84% and a specificity of 88%(Gambhir et al., “A tabulated summary of the FDG PET literature”, J.Nucl. Med. 2001, 42, 1-93S). The imaging of brain tumours, for example,is very difficult owing to the high accumulation of FDG in healthy braintissue.

In some cases, the ¹⁸F-labelled amino acid derivatives currently knownare well suited for the detection of tumours in the brain ((review):Eur. J. Nucl. Med. Mol. Imaging. 2002 May; 29(5): 681-90); however, inthe case of other tumours, they are not able td compete with the imagingproperties of the “Goldstandard” [¹⁸F]2-FDG. The metabolic accumulationand retention of the current F-18-labelled amino acids in tumour tissueis generally lower than of FDG. In addition, the preparation ofisomerically pure F-18-labelled non-aromatic amino acids is chemicallyvery demanding.

Similarly to glucose, for glutamic acid and glutamine, too, an increasedmetabolism in proliferating tumour cells has been described (Medina, J.Nutr. 1131: 2539S-2542S, 2001; Souba, Ann Surg 218: 715-728, 1993). Theincreased rate of protein and nucleic acid syntheses and the energygeneration per se are thought to be the reasons for an increasedglutamine consumption of tumour cells. The synthesis of correspondingC-11- and C-14-labelled compounds, which are thus identical to thenatural substrate, has already been described in the literature (forexample Antoni, Enzyme Catalyzed Synthesis of L-[4-C-11]aspartate andL-[5-C-11]glutamate. J. Labelled Compd. Radiopharm. 44; (4) 2001:287-294 and Buchanan, The biosynthesis of showdomycin: studies withstable isotopes and the determination of principal precursors, J. Chem.Soc. Chem. Commun.; EN; 22; 1984; 1515-1517). First tests with theC-11-labelled compound indicate no significant accumulation in tumours.

It is an object of the present invention to provide novel compoundswhich, in [¹⁸F]-labelled form, are suitable for PET-based diagnosis.

This object is achieved by the provision according to the invention of[¹⁸F]-labelled glutamic acid derivatives and [¹⁸F]-labelled glutaminederivatives of the general formula (I), including diastereomers:

in whichA represents

-   -   a) hydroxyl,    -   b) branched or straight-chain C₁-C₅ alkoxy,    -   c) branched or straight-chain hydroxy C₁-C₅ alkoxy,    -   d) branched or straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄        alkyl)_(n)-O—C₁-C₄ alkyl,    -   e) N(C₁-C₅ alkyl)₂,    -   f) NH₂,    -   g) N(H)-L,    -   h) O-L or    -   i) O—Z,        G represents    -   a) hydroxyl,    -   b) O—Z,    -   c) branched or straight-chain O—C₁-C₅ alkyl,    -   d) branched or straight-chain O—C₂-C₅ alkenyl,    -   e) branched or straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄        alkyl)_(n)-O—C₁-C₄ alkyl,    -   f) branched or straight-chain O—C₂-C₅ alkynyl or    -   g) triphenylmethoxy,        R¹ and R² represent    -   a) hydrogen,    -   b) branched or straight-chain ¹⁸F—C₁-C₅ alkoxy,    -   c) branched or straight-chain ¹⁸F—C₁-C₅ alkyl,    -   d) branched or straight-chain ¹⁸F—C₂-C₅ alkenyl,    -   e) branched or straight-chain ¹⁸F—C₂-C₅ alkynyl,    -   f) hydroxyl,    -   g) branched or straight-chain C₁-C₅ alkyl or    -   h) branched or straight-chain C₁-C₅ alkoxy,    -   alkyl being optionally interrupted by one or more O, S or N,    -   with the proviso that one of the substituents R¹ or R² contains        exactly one ¹⁸F isotope and the respective other substituent        contains no ¹⁸F isotope, with the proviso that R¹ is not        hydrogen,        L represents    -   a) branched or straight-chain C₁-C₅ alkyl,    -   b) branched or straight-chain C₂-C₅ alkenyl,    -   c) branched or straight-chain C₁-C₅ alkyl-(O—C₁-C₄        alkyl)_(n)-O—C₁-C₄ alkyl or    -   d) branched or straight-chain C₂-C₅ alkynyl,        Z represents a metal cation equivalent, and        where n=0, 1, 2 or 3.

Preferred compounds according to the invention of the formula (I) aredistinguished in that

A represents

-   -   a) hydroxyl,    -   b) methoxy,    -   c) ethoxy,    -   d) propoxy,    -   e) NMe₂,    -   f) NEt₂,    -   g) NH₂,    -   h) N(H)-L,    -   i) O-L or    -   j) O—Z.

Further preferred compounds according to the invention of the formula (edistinguished in that

A represents

-   -   a) hydroxyl,    -   b) methoxy,    -   c) ethoxy,    -   d) NMe₂,    -   e) NH₂ or    -   f) N(H)-L.

Particularly preferred compounds according to the invention of theformula (I) are distinguished in that

A represents

-   -   a) hydroxyl,    -   b) branched or straight-chain C₁-C₅ alkoxy or    -   c) NH₂.

Preferred compounds according to the invention of the formula (I) aredistinguished in that

A represents

-   -   hydroxyl.

Preferred compounds according to the invention of the formula (I) aredistinguished in that

A represents

-   -   NH₂.

Preferred compounds according to the invention of the formula (I) aredistinguished in that

A represents

-   -   ethoxy.

Preferred compounds according to the invention of the formula (I) aredistinguished in that

G represents

-   -   a) hydroxyl,    -   b) branched or straight-chain O—C₁-C₄ alkyl or    -   c) O—C₂H₄—OMe.

Further preferred compounds according to the invention of the formula(I) are distinguished in that

G represents

-   -   a) hydroxyl or    -   b) branched or straight-chain O—C₁-C₄ alkyl.

Particularly preferred compounds according to the invention of theformula (I) are distinguished in that

G represents

-   -   a) hydroxyl,    -   or    -   b) ethoxy.

Particularly preferred compounds according to the invention of theformula (I) are distinguished in that

G represents

-   -   hydroxyl.

Preferred compounds according to the invention of the formula (I) aredistinguished in that

R¹ and R² represent

-   -   a) hydrogen,    -   b) branched or straight-chain F—C₁-C₅ alkoxy,    -   c) branched or straight-chain ¹⁸F—C₁-C₅ alkyl,    -   d) branched or straight-chain ¹⁸F—C₃-C₅ alkenyl,    -   e) branched or straight-chain ¹⁸F—C₃-C₅ alkynyl,    -   f) hydroxyl,    -   g) branched or straight-chain C₁-C₅ alkyl or    -   h) branched or straight-chain C₁-C₅ alkoxy.

Preferred compounds according to the invention of the formula (I) aredistinguished in that

R¹ and R² represent

-   -   a) hydrogen,    -   b) branched or straight-chain ¹⁸F—C₂-C₄ alkoxy,    -   c) branched or straight-chain ¹⁸F—C₃-C₅ alkyl,    -   d) branched or straight-chain ¹⁸F—C₃-C₅ alkenyl,    -   e) branched or straight-chain ¹⁸F—C₃-C₅ alkynyl,    -   f) hydroxyl,    -   g) branched or straight-chain C₁-C₅ alkyl or    -   h) branched or straight-chain C₁-C₅ alkoxy,        with the proviso that one of the substituents R¹ or R² contains        exactly one ¹⁸F-isotope and the respective other substituent        contains no ¹⁸F isotope, with the proviso that R¹ is not        hydrogen.

A further particular subject matter of the invention are compounds ofthe general formula I in which

R¹ represents

-   -   a) branched or straight-chain ¹⁸F—C alkoxy,    -   b) branched or straight-chain ¹⁸F—C₃ alkyl.

Straight-chain ¹⁸F—C₂ alkoxy is ¹⁸F-ethoxy.

Straight-chain ¹⁸F—C₃ alkyl is ¹⁸F-propyl.

A further particular subject matter of the invention are compounds ofthe general formula I in which

R¹ represents ¹⁸F-ethoxy or ¹⁸F-propyl and R² represents hydrogen.

Further preferred compounds according to the invention of the formula(I) are distinguished in that

R¹ is selected from the group consisting of ¹⁸F-ethoxy, ¹⁸F-propoxy,¹⁸F-ethyl and ¹⁸F-propyl, and R² is hydrogen.

Preferred compounds according to the invention of the formula (I) aredistinguished in that

L represents

-   -   a) methyl,    -   b) ethyl,    -   c) propyl,    -   d) isopropyl,    -   e) —C₂H₄—OMe or    -   f) —C₂H₄—O—C₂H₄—OMe.

Particularly preferred compounds according to the invention of theformula (I) are distinguished in that

L represents

-   -   a) methyl or    -   b) ethyl.

Compounds according to the invention of the formula (I) which arelikewise preferred are distinguished in that Z is selected from thegroup consisting of Na⁺, K⁺, Ca²⁺ and Mg²⁺. Z is preferably Na⁺.

The process for preparing the compounds according to the invention ofthe general formula (I) is distinguished in that

-   -   one or more protective groups present in a compound of the        formula (II) is/are removed.

Compounds according to formula I:

At physiological pH 7.4, the compounds of the formula (I) according tothe invention may also be present as zwitterions or salts, as is knownto those skilled in the art.

According to a further aspect, the present invention thus relates tocompounds of the general formula (II):

A′ represents

-   -   a) hydroxyl,    -   b) branched or straight-chain C₁-C₅ alkoxy,    -   c) branched or straight-chain hydroxy C₁-C₅ alkoxy,    -   d) branched or straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄        alkyl)_(n)-O—C₁-C₄ alkyl,    -   e) N(C₁-C₅ alkyl)₂,    -   f) NH₂,    -   g) N(H)-L′, or    -   h) O-L′,        G′ represents    -   a) hydroxyl,    -   b) O—Z′,    -   c) branched or straight-chain O—C₁-C₅ alkyl,    -   d) branched or straight-chain O—C₂-C₅ alkenyl,    -   e) branched or straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄        alkyl)_(n)-O—C₁-C₄ alkyl,    -   f) branched or straight-chain O—C₂-C₅ alkynyl or    -   g) triphenylmethoxy,        R¹ and R² represent    -   a) hydrogen,    -   b) branched or straight-chain ¹⁸F—C₁-C₅ alkoxy,    -   c) branched or straight-chain ¹⁸F—C₁-C₅ alkyl,    -   d) branched or straight-chain ¹⁸F—C₂-C₅ alkenyl,    -   e) branched or straight-chain ¹⁸F—C₂-C₅ alkynyl,    -   f) hydroxyl,    -   g) branched or straight-chain C₁-C₅ alkyl or    -   h) branched or straight-chain C₁-C₅ alkoxy,        alkyl being optionally interrupted by one or more O, S or N,        with the proviso that exactly one of the substituents R¹ or R²        contains exactly one ¹⁸F isotope and the respective other        substituent contains no ¹⁸F isotope, with the proviso that R¹ is        not hydrogen,        Q represents    -   a) N(H)-tert-butoxycarbonyl    -   b) N(H)-allyloxycarbonyl,    -   c) N(H)-benzyloxycarbonyl,    -   d) N(H)-ethoxycarbonyl,    -   e) N(H)-methoxycarbonyl,    -   f) N(H)-propoxycarbonyl,    -   e) N(H)-2,2,2-trichloroethoxycarbonyl,    -   f) N(H)-1,1-dimethylpropynyl,    -   g) N(H)-1-methyl-1-phenylethoxycarbonyl,    -   h) N(H)-1-methyl-1-(4-biphenyl)ethoxycarbonyl,    -   i) N(H)-cyclobutylcarbonyl,    -   j) N(H)-1-methylcyclobutylcarbonyl,    -   k) N(H)-vinylcarbonyl,    -   l) N(H)-allylcarbonyl,    -   m) N(H)-adamantylcarbonyl,    -   n) N(H)-diphenylmethylcarbonyl,    -   o) N(H)-cinnamylcarbonyl,    -   p) N(H)-formyl,    -   q) N(H)-benzoyl,    -   r) N(H)-trityl,    -   s) N(H)-p-methoxydiphenylmethyl,    -   t) N(H)-di(p-methoxyphenyl)phenylmethyl,

-   -   v) N-(tert-butoxycarbonyl)₂,        L′ represents    -   a) branched or straight-chain C₁-C₅    -   b) branched or straight-chain C₂-C₅ alkenyl,    -   c) branched or straight-chain C₁-C₅ alkyl-(O—C₁-C₄        alkyl)_(n)-O—C₁-C₄ alkyl or    -   d) branched or straight-chain C₂-C₅ alkynyl,        X′ and X″ independently of one another represent    -   a) branched or straight-chain C₁-C₅ alkyl,    -   b) substituted or unsubstituted aryl,    -   c) substituted or unsubstituted aralkyl or    -   d) substituted or unsubstituted heteroaryl,        Z′ represents a metal cation equivalent, and where n=0, 1, 2 or        3.

Preferred compounds according to the invention of the formula (II) aredistinguished in that

A′ represents

-   -   a) hydroxyl,    -   b) methoxy,    -   c) ethoxy,    -   d) propoxy,    -   e) NMe₂,    -   f) NEt₂,    -   g) NH₂,    -   h) N(H)-L or    -   i) O-L,    -   j) O—Z.

Further preferred compounds according to the invention of the formula(II) are distinguished in that

A′ represents

-   -   a) hydroxyl,    -   b) methoxy,    -   c) ethoxy,    -   d) NMe₂,    -   e) NH₂ or    -   f) N(H)-L.

Particularly preferred compounds according to the invention of theformula (II) are distinguished in that

A′ represents

-   -   a) hydroxyl,    -   b) branched or straight-chain C₁-C₅ alkoxy or    -   c) NH₂.

Preferred compounds according to the invention of the formula (H) aredistinguished in that

A′ represents

-   -   tert-butoxy.

Preferred compounds according to the invention of the formula (II) aredistinguished in that

A′ represents

-   -   NH₂.

Preferred compounds according to the invention of the formula (II) aredistinguished in that

A′ represents

-   -   ethoxy.

Preferred compounds according to the invention of the formula (II) aredistinguished in that

G′ represents

-   -   a) hydroxyl,    -   b) branched or straight-chain O—C₁-C₄ alkyl or    -   c) O—C₂H₄—OMe.

Further preferred compounds according to the invention of the formula(II) are distinguished in that

G′ represents

-   -   a) hydroxyl or    -   b) branched or straight-chain O—C₁-C₄ alkyl.

Particularly preferred compounds according to the invention of theformula (H) are distinguished in that

G′ represents

-   -   a) hydroxyl,    -   b) methoxy,    -   c) ethoxy or    -   d) tert-butoxy.

Particularly preferred compounds according to the invention of theformula (II) are distinguished in that

G′ represents

-   -   tert-butoxy.

Preferred compounds according to the invention of the formula (II) aredistinguished in that

R¹ and R² represent

-   -   a) hydrogen,    -   b) branched or straight-chain ¹⁸F—C₁-C₅ alkoxy,    -   c) branched or straight-chain ¹⁸F—C₁-C₅ alkyl,    -   d) branched or straight-chain ¹⁸F—C₃-C₅ alkenyl,    -   e) branched or straight-chain ¹⁸F—C₃-C₅ alkynyl,    -   f) hydroxyl,    -   g) branched or straight-chain C₁-C₅ alkyl or    -   h) branched or straight-chain C₁-C₅ alkoxy,        with the proviso that exactly one of the substituents R¹ or R²        contains exactly one ¹⁸F-isotope and the respective other        substituent contains no ¹⁸F isotope, with the proviso that R¹ is        not hydrogen.

Preferred compounds according to the invention of the formula (II) aredistinguished in that

R¹ and R² represent

-   -   a) hydrogen,    -   b) branched or straight-chain ¹⁸F—C₂-C₄ alkoxy,    -   c) branched or straight-chain ¹⁸F—C₃-C₅ alkyl,    -   d) branched or straight-chain ¹⁸F—C₃-C₅ alkenyl,    -   e) branched or straight-chain ¹⁸F—C₃-C₅ alkynyl,    -   f) hydroxyl,    -   g) branched or straight-chain C₁-C₅ alkyl or    -   h) branched or straight-chain C₁-C₅ alkoxy,        with the proviso that exactly one of the substituents R¹ or R²        contains exactly one ¹⁸F-isotope and the respective other        substituent is hydrogen, with the proviso that R¹ is not        hydrogen.

Preferred compounds according to the invention of the formula (II) aredistinguished in that R¹ is selected from the group consisting of¹⁸F-ethoxy, ¹⁸F-propoxy, ¹⁸F-ethyl and ¹⁸F-propyl, and R² is hydrogen.

A further particular subject matter of the invention are compounds ofthe general formula II in which

R¹ represents

-   -   a) branched or straight-chain ¹⁸F—C₂ alkoxy or    -   b) branched or straight-chain ¹⁸F—C₃ alkyl.

Straight-chain ¹⁸F—C₂ alkoxy is ¹⁸F-ethoxy.

Straight-chain ¹⁸F—C₃ alkyl is ¹⁸F-propyl,

A further particular subject matter of the invention are compounds ofthe general formula II in which

R¹ represents ¹⁸F-ethoxy or ¹⁸F-propyl and R² represents hydrogen.

Preferred compounds according to the invention of the formula (II) aredistinguished in that L′ represents

-   -   a) methyl,    -   b) ethyl,    -   c) propyl,    -   d) isopropyl,    -   e) —C₂H₄—OMe,    -   f) —C₂H₄—O—C₂H₄—OCH₃ or    -   g) tert-butyl.

Particularly preferred compounds according to the invention of theformula (II) are distinguished in that

L′ represents

-   -   a) methyl,    -   b) ethyl or    -   c) tert-butyl.

Compounds according to the invention of the formula (II) which arelikewise preferred are distinguished in that Z′ is selected from thegroup consisting of Na⁺, K⁺, Ca²⁺ and Mg²⁺. Z′ is preferably Na⁺.

Preferred compounds according to the invention of the formula (II) aredistinguished in that

Q represents

-   -   a) N(H)-tert-butoxycarbonyl,    -   b) N(H)-benzyloxycarbonyl,    -   c) N-(tert-butoxycarbonyl)₂ or

Further preferred compounds according to the invention of the formula(II) are distinguished in that

Q represents

-   -   a) N(H)-tert-butoxycarbonyl,    -   b) N-(tert-butoxycarbonyl)₂ or

Particularly preferred compounds according to the invention of theformula (II) are distinguished in that

Q represents

-   -   a) N(H)-tert-butoxycarbonyl or

Particularly preferred compounds according to the invention of theformula (II) are distinguished in that

Q represents N(H)-tert-butoxycarbonyl.

Preferred compounds according to the invention of the formula (II) aredistinguished in that

X′ and X″ independently of one another represent

-   -   a) branched or straight-chain C₁-C₅ alkyl,    -   b) substituted or unsubstituted aryl or    -   c) substituted or unsubstituted aralkyl.

Further preferred compounds according to the invention of the formula(II) are distinguished in that

X′ and X″ independently of one another represent

-   -   a) branched or straight-chain C₁-C₅ alkyl or    -   b) substituted or unsubstituted aryl.

Particularly preferred compounds according to the invention of theformula (II) are distinguished in that

X′ and X″ represent phenyl or represent phenyl which is substituted inthe 2-position.

The process for preparing the compounds of the general formula (II)according to the invention is distinguished in that the plurality of thecompound according to formula (II) can be formed from a compound of theformula (III) following introduction of the ¹⁸F-isotope.

Process for preparing compounds of the general formula (II) whichcomprises

-   -   reacting a compound of the formula (III) with F-18 fluoride.

Compounds of the formula I, II or III for use as medicament.

Compounds of the formula I, II or III for use for imaging of tumourdisorders.

Use of compounds of the formula I, II or III for preparing a medicamentfor imaging of tumour disorders.

According to a further aspect, the present invention relates tocompounds of the general formula (III):

in whichA″ represents

-   -   a) branched or straight-chain C₁-C₅ alkoxy,    -   b) branched or straight-chain hydroxy C₁-C₅ alkoxy,    -   c) branched or straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄        alkyl)_(n)-O—C₁-C₄ alkyl,    -   d) N(C₁-C₅ alkyl)₂,    -   e) NH₂,    -   f) N(H)-L″, or    -   g) O-L″,        G″ represents    -   a) O—Z″,    -   b) branched or straight-chain O—C₁-C₅ alkyl,    -   c) branched or straight-chain O—C₂-C₅ alkenyl,    -   d) branched or straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄        alkyl)_(n)-O—C₁-C₄ alkyl,    -   e) branched or straight-chain O—C₂-C₅ alkynyl or    -   f) triphenylmethoxy,        R³ and R⁴ represent    -   a) hydrogen,    -   b) branched or straight-chain E-C₁-C₅ alkoxy,    -   c) branched or straight-chain E-C₁-C₅ alkyl,    -   d) branched or straight-chain E-C₂-C₅ alkenyl,    -   e) branched or straight-chain E-C₂-C₅ alkynyl,    -   f) hydroxyl,    -   g) branched or straight-chain C₁-C₅ alkyl or    -   h) branched or straight-chain C₁-C₅ alkoxy,    -   alkyl being optionally interrupted by one or more O, S or N,    -   with the proviso that exactly one of the substituents R³ or R⁴        contains an E and the respective other substituent contains no        E, with the proviso that R³ is not hydrogen,        E represents a leaving group,        Q′ represents    -   a) N(H)-tert-butoxycarbonyl    -   b) N(H)-allyloxycarbonyl,    -   c) N(H)-benzyloxycarbonyl,    -   d) N(H)-ethoxycarbonyl,    -   e) N(H)-methoxycarbonyl,    -   f) N(H)-propoxycarbonyl,    -   g) N(H)-2,2,2-trichloroethoxycarbonyl,    -   h) N(H)-1,1-dimethylpropynyl,    -   i) N(H)-1-methyl-1-phenylethoxycarbonyl,    -   j) N(H)-1-methyl-1-(4-biphenyl)ethoxycarbonyl,    -   k) N(H)-cyclobutylcarbonyl,    -   l) N(H)-1-methylcyclobutylcarbonyl,    -   m) N(H)-vinylcarbonyl,    -   n) N(H)-allylcarbonyl,    -   o) N(H)-adamantylcarbonyl,    -   p) N(H)-diphenylmethylcarbonyl,    -   q) N(H)-cinnamylcarbonyl,    -   r) N(H)-formyl,    -   s) N(H)-benzoyl,    -   t) N(H)-trityl,    -   u) N(H)-p-methoxyphenyldiphenylmethyl,    -   v) N(H)-di(p-methoxyphenyl)phenylmethyl,

-   -   x) N-(tert-butoxycarbonyl)₂,        L″ represents    -   a) branched or straight-chain C₁-C₅ alkyl,    -   b) branched or straight-chain C₂-C₅ alkenyl,    -   c) branched or straight-chain C₁-C₅ alkyl-(O—C₁-C₄        alkyl)_(n)-O—C₁-C₄ alkyl or    -   d) branched or straight-chain C₂-C₅ alkynyl,        X′ and X″ independently of one another represent    -   a) branched or straight-chain C₁-C₅ alkyl,    -   b) substituted or unsubstituted aryl,    -   c) substituted or unsubstituted alkylaryl or    -   d) substituted or unsubstituted heteroaryl,        Z″ represents a metal cation equivalent, and        where n=0, 1, 2 or 3.

Preferred, compounds according to the invention of the general formula(III) are distinguished in that

A″ represents

-   -   a) branched or straight-chain C₁-C₅ alkoxy or    -   b) NH₂.

Further preferred compounds according to the invention of the generalformula (III) are distinguished in that

A″ represents

-   -   a) methoxy,    -   b) ethoxy,    -   c) NH₂ or    -   d) tert-butoxy.

Preferred compounds according to the invention of the general formula(III) are distinguished in that

A″ represents

-   -   methoxy.

Preferred compounds according to the invention of the general formula(III) are distinguished in that

A″ represents

-   -   NH₂.

Preferred compounds according to the invention of the general formula(III) are distinguished in that

A″ represents

-   -   ethoxy.

Preferred compounds according to the invention of the general formula(III) are distinguished in that

A″ represents

-   -   tert-butoxy.

Preferred compounds according to the invention of the general formula(III) are distinguished in that

G″ represents

-   -   a) branched or straight-chain O—C₁-C₅ alkyl,    -   b) branched or straight-chain O—C₂-C₅ alkenyl,    -   c) branched or straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄        alkyl)_(n)-O—C₁-C₄ alkyl or    -   e) triphenylmethoxy.

Further preferred compounds according to the invention of the generalformula (III) are distinguished in that

G″ represents

-   -   a) methoxy,    -   b) ethoxy, or    -   c) tert-butoxy.

Particularly preferred compounds according to the invention of thegeneral formula (III) are distinguished in that

G″ represents

-   -   a) tert-butoxy.

Preferred compounds according to the invention of the general formula(III) are distinguished in that

R³ and R⁴ represent

-   -   a) hydrogen,    -   b) branched or straight-chain E-C₁-C₅ alkoxy,    -   c) branched or straight-chain E-C₁-C₅ alkyl,    -   d) branched or straight-chain E-C₃-C₅ alkenyl,    -   e) branched or straight-chain E-C₃-C₅ alkynyl,    -   f) hydroxyl,    -   g) branched or straight-chain C₁-C₅ alkyl or    -   h) branched or straight-chain C₁-C₅ alkoxy,        with the proviso that exactly one of the substituents R³ or R⁴        contains an E and the respective other substituent contains no        E, with the proviso that R³ is not hydrogen.

Preferred compounds according to the invention of the general formula(III) are distinguished in that

R³ and R⁴ represent

-   -   a) hydrogen,    -   b) branched or straight-chain E-C₂-C₄ alkoxy,    -   c) branched or straight-chain E-C₃-C₅ alkyl,    -   d) branched or straight-chain E-C₃-C₅ alkenyl,    -   e) branched or straight-chain E-C₃-C₅ alkynyl,    -   f) branched or straight-chain C₁-C₅ alkyl or    -   g) branched or straight-chain C₁-C₅ alkoxy,        with the proviso that exactly one of the substituents R³ or R⁴        contains an E and the respective other substituent is hydrogen,        with the proviso that R³ is not hydrogen.

Preferred compounds according to the invention of the general formula(III) are distinguished in that

R³ and R⁴ represent

-   -   a) hydrogen,    -   b) branched or straight-chain E-C₂ alkoxy,    -   c) branched or straight-chain E-C₃ alkyl,    -   d) branched or straight-chain E-C₃ alkenyl or    -   e) branched or straight-chain E-C₃ alkynyl,    -   f) hydroxyl,    -   g) branched or straight-chain C₁-C₅ alkyl or    -   h) branched or straight-chain C₁-C₅ alkoxy,        with the proviso that exactly one of the substituents R⁵ or R⁴        contains an E and the respective other substituent does not        contain an E.

A further particular subject matter of the invention are compounds ofthe general formula III in which

R³ represents

-   -   a) branched or straight-chain E-C₂ alkoxy or    -   b) branched or straight-Chain E-C₃ alkyl.

Straight-chain E-C₂ alkoxy is E-ethoxy.

Straight-chain E-C₃ alkyl is E-propyl.

A further particular subject matter of the invention are compounds ofthe general formula (III) in which

R³ represents E ethoxy or E-propyl and R⁴ represents hydrogen.

E is a leaving group which is known or obvious to the person skilled inthe art and which is described or mentioned, for example, in Synthese(1982), pages 85-125, Table 2, page 86; Carey and Sundberg, OrganischeSynthese, (1995), pages 279-281, Table 5.8; or Netscher, Recent Res.Dev. Org. Chem., 2003, 7, 71-83, schemes 1, 2, 10 and 15 or in JerryMarch, Advanced Organic Chemistry, 4th edition, John Wiley and Sons, pp.351-56 and 642-653), without being limited thereto.

Preferred compounds according to the invention of the general formula(III) are distinguished in that

E represents

-   -   halogen or    -   sulphonyloxy.

Preferred halogens are iodo, bromo and chloro.

Preferred sulphonyloxy are methanesulphonyloxy,trifluoromethanesulphonyloxy, nonafluorobutyloxy, tosyloxy and nosyloxy.

Preferred compounds according to the invention of the general formula(III) are distinguished in that

E represents

-   -   a) chloro,    -   b) bromo,    -   c) methanesulphonyloxy,    -   d) trifluoromethanesulphonyloxy,    -   e) nonafluorobutyloxy,    -   f) tosyloxy or    -   g) iodo.

Preferred compounds according to the invention of the general formula(III) are distinguished in that

E represents

-   -   a) chloro,    -   b) bromo,    -   c) methanesulphonyloxy,    -   d) trifluoromethanesulphonyloxy,    -   e) tosyloxy or    -   f) iodo.

Further preferred compounds according to the invention of the generalformula (Ill) are distinguished in, that

E represents

-   -   a) bromo,    -   b) methanesulphonyloxy,    -   d) trifluoromethanesulphonyloxy.

Particularly preferred compounds according to the invention of thegeneral formula (Ill) are distinguished in that

E represents

-   -   a) bromo, or    -   b) methanesulphonyloxy.

Preferred compounds according to the invention of the general formula(III) are distinguished in that

Q′ represents

-   -   a) N(H)-tert-butoxycarbonyl,    -   b) N(H)-benzyloxycarbonyl,    -   c) N(H)-trityl or

Further preferred compounds according to the invention of the generalformula (III) are distinguished in that

Q′ represents

-   -   a) N(H)-tert-butoxycarbonyl or

Preferred compounds according to the invention of the formula (III) aredistinguished in that

L″ represents

-   -   a) branched or straight-chain C₁-C₅ alkyl,    -   b) branched or straight-chain C₂-C₅ alkenyl or    -   c) branched or straight-chain C₂-C₅ alkynyl.

Preferred compounds according to the invention of the formula (III) aredistinguished in that

L″ represents

-   -   a) methyl,    -   b) ethyl,    -   c) propyl,    -   d) isopropyl,    -   e) —C₂H₄—OMe or    -   f) —C₂H₄—O—C₂H₄—OMe.

Further preferred compounds according to the invention of the formula(III) are distinguished in that

L″ represents

-   -   a) methyl, or    -   b) ethyl.

Preferred compounds according to the invention of the formula (III) aredistinguished in that

X′ and X″ independently of one another represent

-   -   a) branched or straight-chain C₁-C₅ alkyl,    -   b) substituted or unsubstituted aryl or    -   c) aralkyl.

Further preferred compounds according to the invention of the formula(III) are distinguished in that

X′ and X″ independently of one another represent

-   -   a) branched or straight-chain C₁-C₅, alkyl or    -   b) substituted or unsubstituted aryl.

Particularly preferred compounds according to the invention of theformula (III) are distinguished in that

X′ and X″ represent phenyl or phenyl which is substituted in the2-position.

Compounds according to the invention of the formula (III) which arelikewise preferred are distinguished in that Z′ is selected from thegroup consisting of NA⁺, K⁺, Ca²⁺ and Mg²⁺.

Z′ is preferably Na⁺.

According to a further aspect, the present invention thus relates to theuse of compounds of the formula (IV) for preparing compounds of theformula (I) or (II):

in whichG′″ represents

-   -   a) branched or straight-chain O—C₁-C₅ alkyl,    -   b) branched or straight-chain O—C₂-C₅ alkenyl,    -   c) branched or straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄        alkyl)_(n)-O—C₁-C₄ alkyl,    -   d) branched or straight-chain O—C₂-C₅ alkynyl or    -   e) triphenylmethoxy,        R⁵ and R⁶ represent    -   a) hydrogen,    -   b) hydroxyl,    -   c) branched or straight-chain C₁-C₅ alkyl,    -   d) branched or straight-chain C₁-C₅ alkoxy or    -   e) R⁷-E′,        alkyl being optionally interrupted by one or more O, S or N,        with the proviso that exactly one of the substituents R⁵ or R⁶        contains an E′ and the respective other substituent contains no        E′, with the proviso that R⁵ is not hydrogen,        E′ represents a leaving group,        R⁷ represents    -   a) branched or straight-chain C₁-C₅ alkoxy,    -   b) branched or straight-chain C₁-C₅ alkyl,    -   c) branched or straight-chain C₂-C₅ alkenyl or    -   d) branched or straight-chain C₂-C₅ alkynyl,        Q′″ represents    -   a) N-tert-butoxycarbonyl    -   b) N-allyloxycarbonyl,    -   c) N-benzyloxycarbonyl,    -   d) N-ethoxycarbonyl,    -   e) N-methoxycarbonyl,    -   f) N-propoxycarbonyl,    -   g) N-2,2,2-trichloroethoxycarbonyl,    -   h) hydrogen,    -   i) N-1-methyl-1-phenylethoxycarbonyl,    -   j) N-1-methyl-1-(4-biphenylyl)ethoxycarbonyl,    -   k) N-cyclobutylcarbonyl,    -   l) N-1-methylcyclobutylcarbonyl,    -   m) N-vinylcarbonyl,    -   n) N-allylcarbonyl,    -   o) N-adamantylcarbonyl,    -   p) N-diphenylmethylcarbonyl,    -   q) N-cinnamylcarbonyl,    -   r) N-formyl,    -   s) N-benzoyl,    -   t) N(H)-trityl,    -   u) N(H)-p-methoxyphenyldiphenylmethyl,    -   v) N(H)-di(p-methoxyphenyl)phenylmethyl,

-   -   x) N-(tert-butoxycarbonyl)₂,        X′ and X″ independently of one another represent    -   a) branched or straight-chain C₁-C₅ alkyl,    -   b) substituted or unsubstituted aryl,    -   c) substituted or unsubstituted alkylaryl or    -   d) substituted or unsubstituted heteroaryl, and        where n=0, 1, 2 or 3.

Particularly preferred compounds according to the invention of theformula (IV) are distinguished in that

G′″ represents

-   -   a) branched or straight-chain O—C₁-C₅ alkyl,    -   b) branched or straight-chain O—C₂-C₅ alkenyl,    -   c) branched or straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄        alkyl)_(n)-O—C₁-C₄ alkyl or    -   e) triphenylmethoxy.

Further preferred compounds according to the invention of the formula(IV) are distinguished in that

G′″ represents

-   -   a) methoxy,    -   b) ethoxy or    -   c) tert-butoxy.

Particularly preferred compounds according to the invention of theformula (IV) are distinguished in that

G′″ represents

-   -   a) tert-butoxy.

E′ is a leaving group which is known or obvious to the person skilled inthe art And which is described or mentioned, for example, in Synthese(1982), pages 85-125, Table 2, page 86; Carey and Sundberg, OrganischeSynthese, (1995), pages 279-281, Table 5.8; or Netscher, Recent Res.Dev. Org. Chem., 2003, 7, 71-83, schemes 1, 2, 10 and 15 or in JerryMarch, Advanced Organic Chemistry, 4th edition, John Wiley and Sons, pp.351-56 and 642-653), without being limited thereto.

Preferred compounds according to the invention of the general formula(III) are distinguished in that

E′ represents

-   -   halogen or    -   sulphonyloxy.

Preferred halogens are iodo, bromo and chloro.

Preferred sulphonyloxy are methanesulphonyloxy,trifluoromethanesulphonyloxy, nonafluorobutyloxy, tosyloxy and nosyloxy.

Preferred compounds according to the invention of the general formula(IV) are distinguished in that

E′ represents

-   -   a) chloro,    -   b) bromo,    -   c) methanesulphonyloxy,    -   d) trifluoromethanesulphonyloxy,    -   e) nonafluorobutyloxy,    -   f) tosyloxy or    -   g) iodo.

Preferred compounds according to the invention of the general formula(IV) are distinguished in that

E′ represents

-   -   a) chloro,    -   b) bromo,    -   c) methanesulphonyloxy,    -   d) trifluoromethanesulphonyloxy,    -   e) nonafluorobutyloxy    -   f) tosyloxy or    -   g) iodo.

Preferred compounds according to the invention of the formula (IV) aredistinguished in that

E′ represents

-   -   a) bromo,    -   b) methanesulphonyloxy,    -   d) trifluoromethanesulphonyloxy, or    -   c) trifluoromesyloxy.

Further preferred compounds according to the invention of the formula(IV) are distinguished in that

E′ represents

-   -   a) chloro,    -   b) bromo,    -   c) methanesulphonyloxy,    -   d) trifluoromethanesulphonyloxy,    -   e) tosyloxy or    -   f) iodo.

Particularly preferred compounds according to the invention of theformula (IV) are distinguished in that

E′ represents

-   -   a) bromo or    -   b) methanesulphonyloxy.

Preferred compounds according to the invention of the formula (IV) aredistinguished in that

Q′ represents

-   -   a) N(H)-tert-butoxycarbonyl,    -   b) N(H)-benzyloxycarbonyl,    -   c) N(H)-trityl or

Further preferred compounds according to the invention of the formula(IV) are distinguished in that

Q′ represents

-   -   a) N(H)-tert-butoxycarbonyl or

Preferred compounds according to the invention of the formula (IV) aredistinguished in that

X′ and X″ independently of one another represent

-   -   a) branched or straight-chain C₁-C₅ alkyl,    -   b) substituted or unsubstituted aryl or    -   c) aralkyl.

Further preferred compounds according to the invention of the formula(IV) are distinguished in that

X′ and X″ independently of one another represent

-   -   a) branched or straight-chain C₁-C₅ alkyl or    -   b) substituted or unsubstituted aryl.

Particularly preferred compounds according to the invention of theformula (IV) are distinguished in that

X′ and X″ represent phenyl or phenyl which is substituted in the2-position.

Particularly preferred compounds according to the invention of theformula (IV) are distinguished in that

R⁵ and R⁶ represent

-   -   a) hydrogen,    -   b) hydroxyl,    -   c) branched or straight-chain C₁-C₅ alkyl,    -   d) branched or straight-chain C₁-C₅ alkoxy or    -   e) R⁷-E′,        with the proviso that exactly one of the substituents R⁵ or R⁶        contains an E′ and the respective other substituent contains no        E′, with the proviso that R⁵ is not hydrogen.

Particularly preferred compounds according to the invention of theformula (IV) are distinguished in that

R⁵ and R⁶ represent

-   -   a) hydrogen,    -   b) hydroxyl,    -   c) branched or straight-chain C₃-C₅ alkyl,    -   d) branched or straight-chain C₃-C₅ alkoxy or    -   e) R⁷-E′,        with the proviso that exactly one of the substituents R⁵ or R⁶        contains an E′ and the respective other substituent contains no        E′,        E′ represents    -   a) chloro,    -   b) bromo,    -   c) mesyloxy,    -   d) trifluoromethylsulphonyloxy,    -   e) nonafluorobutyloxy,    -   f) tosyloxy or    -   g) iodo,        R⁷ represents    -   a) branched or, straight-chain C₁-C₅ alkoxy,    -   b) branched or straight-chain C₁-C₅ alkyl,    -   c) branched or straight-chain C₂-C₅ alkenyl or    -   d) branched or straight-chain C₂-C₅ alkynyl.

Invention compounds of formula I, II and III are 2S glutamic acid orglutamine derivatives (L-glutamic acid or glutamine derivatives).

According to a further aspect, the present invention relates to animaging kit comprising compounds of the general formula III or IV.

According to a further aspect, the present invention relates topharmaceutical compositions comprising compounds of the general formulaI, II, III or IV and suitable pharmaceutical carrier substances.

Compounds of the formula I or II are characterized in that the compoundsare suitable for imaging in a dosage range of 37-600 MBq.

Preferred compounds of the formula I or II are characterized in that thecompounds are particularly suitable in a dosage range of 150 MBq-370MBq.

Compounds of the formula I or II for the use as medicament.

Compounds of the formula I or II for use for the imaging in tumourdisorders.

Use of compounds of the formula I, II, III or IV for producing amedicament for the imaging in tumour disorders.

The process for preparing the compounds of the general formula (I) or(II) according to the invention is distinguished in that most of thecompounds of the formula (I) or (II) can be formed by introducing the¹⁸F isotope into a compound of the general formula (IV).

The present invention relates to compounds of the general formula (IV).

Particularly preferred for introducing the ¹⁸F isotope are

4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane K18F (croneether salt Kryptofix K18F),

K¹⁸F, H¹⁸F, KH¹⁸F₂, Cs¹⁸F, Na¹⁸F or

¹⁸F tetraalkylammonium salt (for example [F-18]tetrabutylammoniumfluoride).

The present invention relates to compounds of the general formula (I) or(II) and processes wherein the fluorine isotope ¹⁸F is used.

If a compound of the formula (I), the formula (II), the formula (III),or the formula (IV) of the present subject matter of the inventioncontains one or more centres of chirality, the present inventionembraces all forms of this isomer including all possible diastereomers,with the proviso that the substituent R¹-R⁶ is present in Sconfiguration. In cases where a carbon-carbon double bond is present,both the “cis” and “trans” isomer form part of the present invention. Incases where tautomeric forms may be present, such as, for example,keto-enol tautomerism, the present invention embraces all tautomericforms, but these forms may be present in equilibrium or, preferably, inone form.

The compounds of the general formulae I and II and their preferredembodiments are used as medicaments.

The compounds of the general formula I or II according to the inventionand their preferred embodiments are used in the diagnosis/imaging ofphysiological or pathological conditions.

These compounds are preferably used in the non-invasive PET-baseddiagnosis on the human or animal body.

Particularly preferably, the compounds of the general formula I or IIaccording to the invention and their preferred embodiments are used inthe diagnosis of tumour disorders. Examples of such tumour disorders aremalignomas of the gastrointestinal or colorectal tract, liver carcinoma,pancreas carcinoma, kidney carcinoma, bladder carcinoma, thyroidcarcinoma, prostrate carcinoma, endometrial carcinoma, ovary carcinoma,testes carcinoma, melanoma, small-cell and non-small-cell bronchialcarcinoma, dysplastic oral mucosa carcinoma, invasive oral cancer;breast cancer, including hormone-dependent and hormone-independentbreast cancer, squamous cell carcinoma, neurological cancer disordersincluding neuroblastoma, glioma, astrocytoma, osteosarcoma, meningioma,soft tissue sarcoma; haemangioma and endocrine tumours, includingpituitary adenoma, chromocytoma, paraganglioma, haematological tumourdisorders including lymphoma and leukaemias; or metastases of one of thetumours mentioned above.

The compounds of the general formula I or II according to the inventionand their preferred embodiments are used for preparing a medicament forthe diagnosis of tumour disorders. Examples of such tumour disorders aremalignomas of the gastrointestinal or colorectal tract, liver carcinoma,pancreas carcinoma, kidney carcinoma, bladder carcinoma, thyroidcarcinoma, prostrate carcinoma, endometrial carcinoma, ovary carcinoma,testes carcinoma, melanoma, small-cell and non-small-cell bronchialcarcinoma, dysplastic oral mucosa carcinoma, invasive oral cancer;breast cancer, including hormone-dependent and hormone-independentbreast cancer, squamous cell carcinoma, neurological cancer disordersincluding neuroblastoma, glioma, astrocytoma, osteosarcoma, meningioma,soft tissue sarcoma; haemangioma and endocrine tumours, includingpituitary adenoma, chromocytoma, paraganglioma, haematological tumourdisorders including lymphoma and leukaemias; or metastases of one of thetumours mentioned above.

The invention relates to pharmaceutical preparations comprising at leastone compound of the formula I, II, III or IV and also a pharmaceuticallyacceptable carrier.

To the use of the compounds of the formula I, II, III or IV asmedicaments, they are brought into the form of a pharmaceuticalpreparation which, in addition to the active compound, comprisespharmaceutical organic or inorganic inert carrier materials suitable forenteral or parenteral administration, such as, for example, water,gelatine, gum Arabic, lactose, starch, magnesium stearate, talcum,vegetable oils, polyalkylene glycols, etc.

The invention relates to a kit comprising at least one compound of theformula I, II, Ill, or IV.

-   1) Compounds of the general formula I

in whichA represents

-   -   a) hydroxyl,    -   b) branched or straight-chain C₁-C₅ alkoxy,    -   c) branched or straight-chain hydroxy C₁-C₅ alkoxy,    -   d) branched or straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄        alkyl)_(n)-O—C₁-C₄ alkyl,    -   e) N(C₁-C₅ alkyl)₂,    -   f) NH₂,    -   g) N(H)-L,    -   h) O-L or    -   i) O—Z,        G represents    -   a) hydroxyl,    -   b)    -   b) branched, or straight-chain O—C₁-C₅ alkyl,    -   c) branched or straight-chain O—C₂-C₅ alkenyl,    -   d) branched or straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄        alkyl)_(n)-O—C₁-C₄ alkyl,    -   e) branched or straight-chain O—C₂-C₅ alkynyl or    -   f) triphenylmethoxy,        R¹ and R² represent    -   a) hydrogen,    -   b) branched or straight-chain ¹⁸F—C₂-C₅ alkoxy,    -   c) branched or straight-chain ¹⁸F—C₁-C₅ alkyl,    -   d) branched or straight-chain ¹⁸F—C₂-C₅ alkenyl,    -   e) branched or straight-chain ¹⁸F—C₂-C₅ alkynyl,    -   f) hydroxyl,    -   g) branched or straight-chain C₁-C₅ alkyl or    -   h) branched or straight-chain C₁-C₅ alkoxy,    -   with the proviso that one of the substituents R¹ or R² contains        exactly one ¹⁸F isotope and the respective other substituent        contains no ¹⁸F isotope, with the proviso that R¹ is not        hydrogen,        L represents    -   a) branched or straight-chain C₁-C₅ alkyl,    -   b) branched or straight-chain C₂-C₅ alkenyl,    -   c) branched or straight-chain C₁-C₅ alkyl-(O—C₁-C₄        alkyl)_(n)-O—C₁-C₄ alkyl or    -   d) branched or straight-chain C₂-C₅ alkynyl,    -   Z represents a metal cation equivalent, and    -   where n=0, 1, 2 or 3.

-   2) Compounds according to Claim 1, characterized in that A    represents hydroxyl, branched or straight-chain C₁-C₅ alkoxy or NH₂.

-   3) Compound according to Claim 1 or 2, characterized in that A    represents NH₂.

-   4) Compounds according to any of Claims 1 to 3, characterized in    that R¹ is selected from the group consisting of ¹⁸F-methoxy,    ¹⁸F-ethoxy, ¹⁸F-propoxy, ¹⁸F-ethyl and ¹⁸F-propyl, and R² is    hydrogen.

-   5) Compound according to any of Claims 1 to 3, characterized in that    R¹ represents ¹⁸F and R² represents hydrogen.

-   6) Compound according to any of Claims 1 to 5, characterized in that    G is selected from the group consisting of hydroxyl and branched or    straight-chain O—C₁-C₄ alkyl.

-   7) Compound according to Claim 6, characterized in that G is    methoxy.

-   8) Compound according to any of Claims 1 to 7, characterized in that    Z is selected from the group consisting of Mg²⁺, Ca²⁺, Na⁺ and K⁺.

-   9) Compound according to Claim 1, selected from the group of    compounds of the formulae:

-   10) Compounds of the general formula (II):

-   -   in which    -   A′ represents        -   a) hydroxyl,        -   b) branched or straight-chain C₁-C₅ alkoxy,        -   c) branched or straight-chain hydroxy C₁-C₅ alkoxy,        -   d) branched or straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄            alkyl)_(n)-O—C₁-C₄ alkyl,        -   e) N(C₁-C₅ alkyl)₂,        -   f) NH₂,        -   g) N(H)-L′,        -   h) O-L′,    -   G′ represents        -   a) hydroxyl,        -   b) O—Z′,        -   c) branched or straight-chain O—C₁-C₅ alkyl,        -   d) branched or straight-chain O—C₂-C₅ alkenyl,        -   e) branched or straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄            alkyl)_(n)-O—C₁-C₄ alkyl,        -   f) branched or straight-chain O—C₂-C₅ alkynyl or        -   g) triphenylmethoxy,    -   R¹ and R² represent        -   a) hydrogen,        -   i) branched or straight-chain ¹⁸F—C₂-C₅ alkoxy,        -   j) branched or straight-chain ¹⁸F—C₁-C₅ alkyl,        -   k) branched or straight-chain ¹⁸F—C₂-C₅ alkenyl,        -   l) branched or straight-chain ¹⁸F—C₂-C₅ alkynyl,        -   m) hydroxyl,        -   n) branched or straight-chain C₁-C₅ alkyl or        -   o) branched or straight-chain C₁-C₅ alkoxy,        -   with the proviso that exactly one of the substituents R¹ or            R² contains exactly one ¹⁸F isotope and the respective other            substituent contains no ¹⁸F isotope,        -   with the proviso that R¹ is not hydrogen,    -   Q represents        -   a) N(H)-tert-butoxycarbonyl,        -   b) N(H)-allyloxycarbonyl,        -   c) N(H)-benzyloxycarbonyl,        -   d) N(H)-ethoxycarbonyl,        -   e) N(H)-methoxycarbonyl,        -   f) N(H)-propoxycarbonyl,        -   e) N(H)-2,2,2-trichloroethoxycarbonyl,        -   f) N(H)-1,1-dimethylpropynyl,        -   g) N(H)-1-methyl-1-phenylethoxycarbonyl,        -   h) N(H)-1-methyl-1-(4-biphenyl)ethoxycarbonyl,        -   i) N(H)-cyclobutylcarbonyl,        -   j) N(H)-1-methylcyclobutylcarbonyl,        -   k) N(H)-vinylcarbonyl,        -   l) N(H)-allylcarbonyl,        -   m) N(H)-adamantylcarbonyl,        -   n) N(H)-diphenylmethylcarbonyl,        -   o) N(H)-cinnamylcarbonyl,        -   p) N(H)-formyl,        -   q) N(H)-benzoyl,        -   r) N(H)-trityl,        -   s) N(H)-p-methoxydiphenylmethyl,        -   t) N(H)-di(p-methoxyphenyl)phenylmethyl,

-   -   -   v) N-(tert-butoxycarbonyl)₂,

    -   L′ represents        -   a) branched or straight-chain C₁-C₅ alkyl,        -   b) branched or straight-chain C₂-C₅ alkenyl,        -   c) branched or straight-chain C₁-C₅ alkyl-(O—C₁-C₄            alkyl)_(n)-O—C₁-C₄ alkyl or        -   d) branched or straight-chain C₂-C₅ alkynyl,

    -   X′ and X″ independently of one another represent        -   a) branched or straight-chain C₁-C₅ alkyl,        -   b) substituted or unsubstituted aryl,        -   c) substituted or unsubstituted aralkyl or        -   d) substituted or unsubstituted heteroaryl,

    -   Z′ represents a metal cation equivalent, and

    -   where n=0, 1, 2 or 3.

-   11) Compounds according to Claim 10, characterized in that A′    represents hydroxyl, branched or straight-chain C₁-C₅ alkoxy or NH₂.

-   12) Compounds according to Claim 11, characterized in that A′    represents methoxy.

-   13) Compounds according to any of Claims 10 to 12, characterized in    that R¹ is selected from the group consisting of ¹⁸F-ethoxy,    ¹⁸F-propoxy, ¹⁸F-ethyl, and ¹⁸F-propyl, and R² is hydrogen.

-   14) Compound according to any of Claims 10 to 13, characterized in    that G is selected from the group consisting of hydroxyl, and    branched or straight-chain O—C₁-C₄ alkyl.

-   15) Compound according to Claim 14, characterized in that G    represents methoxy.

-   16) Compound according to any of Claims 10 to 15, characterized in    that Z′ is selected from the group consisting of Na⁺, K⁺, Ca²⁺ and    Mg²⁺.

-   17) Compound according to any of Claims 10 to 16, characterized in    that Q is selected from the group consisting of    N(H)-tert-butoxycarbonyl, N(H)-benzyloxycarbonyl and

-   -   in which    -   X′ and X″ independently of one another represent        -   a) branched or straight-chain C₁-C₅ alkyl,        -   b) substituted or unsubstituted aryl,        -   c) substituted or unsubstituted aralkyl or        -   d) substituted or unsubstituted heteroaryl.

-   18) Compound according to Claim 17 characterized in that Q    represents N(H)-tert-butoxycarbonyl.

-   19) Process for preparing compounds of the general formula (I)    according to any of Claims 1 to 9,    -   which comprises        -   removing one or more protective groups present in a compound            of the formula (II) according to any of claims 10 to 18.

-   20) Process for preparing compounds of the general formula (II)    according to any of Claims 10 to 18,    -   which comprises        -   reacting a compound of the formula (III) according to Claim            24 with F-18 fluoride.

-   21) Compounds according to any of Claims 1 to 18 for use as    medicaments.

-   22) Compounds according to any of Claims 1 to 18 for use for imaging    in tumour disorders.

-   23) Use of compounds according to any of Claims 1 to 18 for    preparing a medicament for imaging in tumour disorders.

-   24) Compounds of the formula (III)

-   -   in which    -   A″ represents        -   a) branched or straight-chain C₁-C₅ alkoxy,        -   b) branched or straight-chain hydroxy C₁-C₅ alkoxy,        -   c) branched or straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄            alkyl)_(n)-O—C₁-C₄ alkyl,        -   d) N(C₁-C₅ alkyl)₂,        -   e) NH₂,        -   f) N(H)—U′        -   g) N(H)-L″, or        -   h) O-L″,    -   G″ represents        -   a) O—Z″,        -   b) branched or straight-chain O—C₁-C₅ alkyl,        -   c) branched or straight-chain O—C₂-C₅ alkenyl,        -   d) branched or straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄            alkyl)_(n)-O—C₁-C₄ alkyl, e) branched or straight-chain            O—C₂-C₅ alkynyl or        -   f) triphenylmethoxy,    -   R³ and R⁴ represent        -   a) hydrogen,        -   b) branched or straight-chain E-C₂-C₅ alkoxy,        -   c) branched or straight-chain E-C₁-C₅ alkyl,        -   d) branched or straight-chain E-C₂-C₅ alkenyl,        -   e) branched or straight-chain E-C₂-C₅ alkynyl,        -   f) hydroxyl,        -   g) branched or straight-chain C₁-C₅ alkyl or        -   h) branched or straight-chain C₁-C₅ alkoxy,        -   with the proviso that exactly one of the substituents R³ or            R⁴ contains an E and the respective other substituent            contains no E, with the proviso that R³ is not hydrogen,    -   E represents        -   a) chloro,        -   b) bromo,        -   c) methanesulphonyloxy,        -   d) trifluoromethylsulphonyloxy,        -   e) nonafluorobutyloxy,        -   f) tosyloxy or        -   g) iodo,    -   Q′ represents        -   a) N(H)-tert-butoxycarbonyl        -   b) N(H)-allyloxycarbonyl,        -   c) N(H)-benzyloxycarbonyl,        -   d) N(H)-ethoxycarbonyl,        -   e) N(H)-methoxycarbonyl,        -   f) N(H)-propoxycarbonyl,        -   g) N(H)-2,2,2-trichloroethoxycarbonyl,        -   h) N(H)-1,1-dimethylpropynyl,        -   i) N(H)-1-methyl-1-phenylethoxycarbonyl,        -   j) N(H)-1-methyl-1-(4-biphenylyl)ethoxycarbonyl,        -   k) N(H)-cyclobutylcarbonyl,        -   l) N(H)-1-methylcyclobutylcarbonyl,        -   m) N(H)-vinylcarbonyl,        -   n) N(H)-allylcarbonyl,        -   o) N(H)-adamantylcarbonyl,        -   p) N(H)-diphenylmethylcarbonyl,        -   q) N(H)-cinnamylcarbonyl,        -   r) N(H)-formyl,        -   s) N(H)-benzoyl,        -   t) N(H)-trityl,        -   u) N(H)-p-methoxydiphenylmethyl,        -   v) N(H)-di(p-methoxyphenyl)phenylmethyl,

-   -   -   x) N-(tert-butoxycarbonyl)₂,

    -   L″ represents        -   a) branched or straight-chain C₁-C₅ alkyl,        -   b) branched or straight-chain C₂-C₅ alkenyl,        -   c) branched or straight-chain C₁-C₅ alkyl-(O—C₁-C₄            alkyl)_(n)-O—C₁-C₄ alkyl or        -   d) branched or straight-chain C₂-C₅ alkynyl,

    -   X′ and X″ independently of one another represent        -   a) branched or straight-chain C₁-C₅ alkyl,        -   b) substituted or unsubstituted aryl,        -   c) substituted or unsubstituted alkylaryl or        -   d) substituted or unsubstituted heteroaryl,

    -   Z″ represents a metal cation equivalent, and

    -   where n=0, 1, 2 or 3.

-   25) Use of compounds of the formula (IV) for preparing compounds of    the formula (I) or (II):

-   -   in which    -   G′″ represents        -   a) branched or straight-chain O—C₁-C₅ alkyl,        -   b) branched or straight-chain O—C₂-C₅ alkenyl,        -   c) branched or straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄            alkyl)_(n)-O—C₁-C₄ alkyl,        -   d) branched or straight-chain O—C₂-C₅ alkynyl or        -   e) triphenylmethoxy,    -   R⁵ and R⁶ represent        -   a) hydrogen,        -   b) hydroxyl,        -   c) branched or straight-chain C₁-C₅ alkyl,        -   d) branched or straight-chain C₁-C₅ alkoxy or        -   e) R⁷-E,        -   with the proviso that exactly one of the substituents R⁵ or            R⁶ contains an E′ and the respective other substituent            contains no E′, with the proviso that R⁵ is not hydrogen,    -   E′ represents        -   a) chloro,        -   b) bromo,        -   c) methanesulphonyloxy,        -   d) trifluoromethanesulphonyloxy,        -   e) nonafluorobutyloxy,        -   f) tosyloxy or        -   g) iodo,    -   R⁷ represents        -   a) branched or straight-chain C₂-C₅ alkoxy,        -   b) branched or straight-chain C₁-C₅ alkyl,        -   c) branched or straight-chain C₂-C₅ alkenyl or        -   d) branched or straight-chain C₂-C₅ alkynyl,    -   Q′″ represents        -   a) N-tert-butoxycarbonyl        -   b) N-allyloxycarbonyl,        -   c) N-benzyloxycarbonyl,        -   d) N-ethoxycarbonyl,        -   e) N-methoxycarbonyl,        -   f) N-propoxycarbonyl,        -   g) N-2,2,2-trichloroethoxycarbonyl,        -   h) hydrogen,        -   i) N-1-methyl-1-phenylethoxycarbonyl,        -   j) N-1-methyl-1-(4-biphenylyl)ethoxycarbonyl,        -   k) N-cyclobutylcarbonyl, 1) N-1-methylcyclobutylcarbonyl,        -   m) N-vinylcarbonyl,        -   n) N-allylcarbonyl,        -   o) N-adamantylcarbonyl,        -   p) N-diphenylmethylcarbonyl,        -   q) N-cinnamylcarbonyl,        -   r) N-formyl,        -   s) N-benzoyl,        -   t) N(H)-trityl,        -   u) N(H)-p-methoxyphenyldiphenylmethyl,        -   v) N(H)-di(p-methoxyphenyl)phenylmethyl,

-   -   -   x) N-(tert-butoxycarbonyl)₂,

    -   X′ and X″ independently of one another represent        -   a) branched or straight-chain C₁-C₅ alkyl,        -   b) substituted or unsubstituted aryl,        -   c) substituted or unsubstituted alkylaryl or        -   d) substituted or unsubstituted heteroaryl, and

    -   where n=1, 2 or 3.

-   14) Imaging kit, comprising compounds of the general formula III or    IV.

-   15) Pharmaceutical composition, comprising compounds of the general    formula I, II, III or IV and suitable pharmaceutical carrier    substances.

-   30) Compounds according to any of Claims 1 to 9, 10 to 18, and    compounds of the general formula IV, characterized in that the    compounds are suitable for imaging in a dosage range of 37-600 MBq.

-   31) Compounds according to claim 30, characterized in that the    compounds are particularly suitable in a dosage range of 150 MBq-370    MBq.

Compounds according to the invention in which the [F-18]-isotope ispositioned via a methylene group in the 4-position of the glutamic acidskeleton, such as, for example, in 4S—[F-18]fluoromethylglutamic acid 1,can be prepared as shown in Scheme 7. Thus, for example, the acidicremoval of the protective groups of the compound 2 affords the compound4S—[F-18]fluoromethylglutamic acid 1 according to the invention.

Here, various organic (for example trifluoroacetic acid), but especiallyinorganic acids, such as, for example, hydrobromic acid, hydrochloricacid, sulphuric acid, perchloric acid or phosphoric acid may be used.The compound 2 according to the invention of the formula (I) can bepurified by HPLC, where, in principle, various purification steps may becarried out upstream or downstream, such as, for example, purificationon a RP-C18 cartridge or other separating materials.

The radiochemical fluorination of tosylate 3, which is synthesizedanalogously to the method described in the literature (Chem. Pharm.Bull., 17, 5 (1969), 879-885) from 4 (Tetrahedron, 45, 5, (1989)1453-1464), to the [F-18]-labelled glutamic acid derivative 2 can becarried out using methods known to the person skilled in the art (seeScheme 8).

Here, compound 3 can be reacted in the presence of a base, such as, forexample, tetraalkylammonium carbonate and tetraalkylphosphoniumcarbonate and potassium carbonate, etc., with the appropriate[F-18]-fluoride solution. The reaction is preferably carried out atelevated temperatures. The addition of crone ethers, such as, forexample, Kryptofix (K2.2.2), may have a positive effect on the reaction,in particular in combination with K₂CO₃ as catalyzing base. Possiblesolvents are preferably aprotic, but it is also possible to use proticsolvents or else aprotic solvent additives, such as, for example, water.Usually, acetonitrile, dimethyl sulphoxide or dimethylformamide are usedas the most suitable solvents for the radiochemical fluorination with[F-18]-fluoride anions. Usually, compound 2 does not have to besubjected to a purification but can be treated instantly using themethods described for the conversion of 2 into 1. However, apurification of the compound 2 is possible in principle, preferablyusing preparative HPLC with a nonpolar phase, such as, for example, RPC-18.

Compounds according to the invention in which the [F-18]-isotope ispositioned via an alkoxy group in the 4S-configuration in the 4-positionof the glutamic acid skeleton, such as, for example, in4-S-(2[F-18]fluoroethoxyglutamic acid (5), can be prepared as shown inScheme 9. Thus, for example, the acidic removal of the protective groupsof the compound 6 or (7) affords the compound4-S—[F-18]fluoroethoxyglutamic acid (5) according to the invention.

Here, various organic (for example trifluoroacetic acid), but especiallyinorganic acids, such as, for example, hydrobromic acid, hydrochloricacid, sulphuric acid, perchloric acid or phosphoric acid may be used.Also possible is a basic ring opening of 6 using lithium hydroxide,sodium hydroxide, potassium hydroxide, etc. (S. Baker et al. TetrahedronLett. 1998, 39, 2815-2818).

The compound 5 according to the invention of the formula (I) can bepurified by HPLC, where, in principle, various purification steps may becarried out upstream or downstream, such as, for example, purificationon a RP-C18 cartridge or other separating materials.

The radiochemical fluorination of tosylate 8, which is synthesizedanalogously to the method described in the literature (N. Sharma et al.Tetrahedron Lett. 2004, 45, 1403-1406) from 9, to the [F-18]-labelledS-glutamic acid derivative 6 can be carried out using methods known tothe person skilled in the art (see Scheme 10).

Here, compound 6 can be reacted in the presence of a base, such as, forexample, tetraalkylammonium carbonate and tetraalkylphosphoniumcarbonate and potassium carbonate, etc., with the appropriate[F-18]-fluoride solution. The reaction is preferably carried out atelevated temperatures. The addition of crone ethers, such as, forexample, Kryptofix (K2.2.2), may have a positive effect on the reaction,in particular in combination with K₂CO₃ as catalyzing base. Possiblesolvents are preferably aprotic, but it is also possible to use proticsolvents or else aprotic solvent additives, such as, for example, water.Usually, acetonitrile, dimethyl sulphoxide or dimethylformamide are usedas the most suitable solvents for the radiochemical fluorination with[F-18]-fluoride anions. Usually, compound 6 does not have to besubjected to a purification but can be treated instantly using themethods described for the conversion of 6 into 5. However, apurification of the compound 6 is possible in principle, preferablyusing preparative HPLC with a nonpolar phase, such as, for example, RPC-18. Also possible is a purification using cartridges.

The radiochemical fluorination of tosylate 10; which is synthesizedanalogously to the method described in the literature (X. ZhangTetrahedron Lett. 2001, 42, 5335-5338) from 8, to the [F 18]-labelledglutamic acid derivative 7 can be carried out by methods known to theperson skilled in the art (see Scheme 11).

Here, compound 10 can be reacted in the presence of a base, such as, forexample, tetraalkylammonium carbonate and tetraalkylphosphoniumcarbonate and potassium carbonate, etc., with the appropriate[F-18]-fluoride solution. The reaction is preferably carried out atelevated temperatures. The addition of crone ethers, such as, forexample, Kryptofix (K2.2.2), may have a positive effect on the reaction,in particular in combination with K₂CO₃ as catalyzing base. Possiblesolvents are preferably aprotic, but it is also possible to use proticsolvents or else aprotic solvent additives, such as, for example, water.Usually, acetonitrile, dimethyl sulphoxide or dimethylformamide are usedas the most suitable solvents for the radiochemical fluorination with[F-18]-fluoride anions. Usually, compound 7 does not have to besubjected to a purification but can be treated instantly using themethods described for the conversion of 7 into 5. However, apurification of the compound 7 is possible in principle, preferablyusing preparative HPLC with a nonpolar phase, such as, for example, RPC-18. Also possible is a purification using cartridges.

Another suitable starting material for the radiochemical fluorination to6 is the bromide 8a which can be obtained from 9 in two steps: byalkylation of 9 using 1,2-dibromoethane to give thebromoethoxypyrrolidine derivative 8b and subsequent oxidation using, forexample, ruthenium(III) compounds, as described in Examples 3a and 3b.

The synthesis of F-19 reference compounds 11, 12 and 13 can be carriedout as shown in Scheme 12.

11 can be obtained by alkylating and oxidizing the hydroxyprolinederivative 9. For preparing F-19 reference compounds, it has also beenfound to be advantageous to prepare the fluorides from analogoushydroxyl compounds using DAST (diethylaminosulphur trifluoride)according to methods known to the person skilled in the art, asdescribed, for example, in Example 1d.

Ring-opening of the pyroglutamine derivative 26 gives the open-chainreference compound 12. The acidic removal of the protective groups leadsto the glutamic acid derivative 13.

Compounds according to the invention in which the [F-18]-isotope ispositioned via an alkyl group into the 4-position of the glutamic acidskeleton, such as, for example, 4-[F-18]fluoropropylglutamic acid 14 or4-[F-18]fluorobutylglutamic acid 15, can be prepared as shown in Scheme13. Thus, for example, the acidic removal of the protective groups ofcompounds 16 and 17 gives the compounds according to the invention4-[F-18]fluoropropylglutamic acid 14 and 4-[F-18]fluorobutylglutamicacid 15, respectively.

Here, various organic (for example trifluoroacetic acid), but especiallyinorganic acids, such as, for example, hydrobromic acid, hydrochloricacid, sulphuric acid, perchloric acid or phosphoric acid may be used.The compounds 14 and 15 according to the invention of the formula (I)can be purified by HPLC, where, in principle, various purification stepsmay be carried out upstream or downstream, such as, for example,purification using an RP-C18 cartridge or other separating materials.

The radiochemical fluorination of bromide 18 or tosylate 19, which aresynthesized analogously to the method described in the literature (S.Hanessian, et al. J. Org. Chem. 2005, 70, 5070-5085) from 20, to the[F-18]-labelled glutamic acid derivatives 16 and 17 can be carried outby methods known to the person skilled in the art (see Scheme 14).

Here, compounds 18 and 19 can be reacted in the presence of a base, suchas, for example, tetraalkylammonium carbonate and tetraalkylphosphoniumcarbonate and potassium carbonate, etc., with the appropriate[F-18]-fluoride solution. The reaction is preferably carried out atelevated temperatures. The addition of crone ethers, such as, forexample, Kryptofix (K2.2.2), may have a positive effect on the reaction,in particular in combination with K₂CO₃ as catalyzing base. Possiblesolvents are preferably aprotic, but it is also possible to use proticsolvents or else aprotic solvent additives, such as, for example, water.Usually, acetonitrile, dimethyl sulphoxide or dimethylformamide are usedas the most suitable solvents for the radiochemical fluorination with[F-18]-fluoride anions. Usually, compounds 16 and 17 do not have to besubjected to a purification but can be treated instantly using themethods described for the conversion of 16 into 14 or 17 into 15.However, a purification of the compounds 16 and 17 is possible inprinciple, preferably using preparative HPLC with a nonpolar phase, suchas, for example, RP C-18.

The F-19 reference compounds 21 and 22 can be synthesized by alkylationof the glutamic acid derivative 20 (Scheme 15). Compound 20 can also bealkylated using iodides, preferably diiodides, analogously to Example2a. In this case, a precursor suitable for radiochemical fluorination isobtained in one step from the commercially available glutamic acidderivative 20.

Removal of the protective groups affords the fluoroalkylated glutamicacid derivatives 23 and 24.

In each case, the C-3 or/and C4 position of a compound of the formula(I), the formula (II), the formula (III), the formula (IV) or theformula (V) of the present subject matter of the invention shouldcontain the S-forms of the centres of chirality. In cases where acarbon-carbon double bond is present, both the “cis” and “trans” isomerform part of the present invention. In cases where tautomeric forms maybe present, such as, for example, keto-enol tautomerism, the presentinvention embraces all tautomeric forms, but these forms may be presentin equilibrium or, preferably, in one form.

The compounds of the general formulae I or II and their preferredembodiments are used as medicaments.

The compounds of the general formula I or II according to the inventionand their preferred embodiments are used in the diagnosis ofphysiological or pathological conditions.

These compounds are preferably used in the non-invasive PET-baseddiagnosis on the human or animal body.

Particularly preferably, the compounds of the general formula I or IIaccording to the invention and their preferred embodiments are used inthe diagnosis of tumour disorders; Examples of such tumour disorders aremalignomas of the gastrointestinal or colorectal tract, liver carcinoma,pancreas carcinoma, kidney carcinoma, bladder carcinoma, thyroidcarcinoma, prostrate carcinoma, endometrial carcinoma, ovary carcinoma,testes carcinoma, melanoma, small-cell and non-small-cell bronchialcarcinoma, dysplastic oral mucosa carcinoma, invasive oral cancer;breast cancer, including hormone-dependent and hormone-independentbreast cancer, squamous cell carcinoma, neurological cancer disordersincluding neuroblastoma, glioma, astrocytoma, osteosarcoma, meningioma,soft tissue sarcoma; haemangioma and endocrine tumours, includingpituitary adenoma, chromocytoma, paraganglioma, haematological tumourdisorders including lymphoma and leukaemias; or metastases of one of thetumours mentioned above.

The compounds of the general formula I or II according to the inventionand their preferred embodiments are used for preparing a medicament forthe diagnosis of tumour disorders. Examples of such tumour disorders aremalignomas of the gastrointestinal or colorectal tract, liver carcinoma,pancreas carcinoma, kidney carcinoma, bladder carcinoma, thyroidcarcinoma, prostrate carcinoma, endometrial carcinoma, ovary carcinoma,testes carcinoma, melanoma, small-cell and non-small-cell bronchialcarcinoma, dysplastic oral mucosa carcinoma, invasive oral cancer;breast cancer, including hormone-dependent and hormone-independentbreast cancer, squamous cell carcinoma, neurological cancer disordersincluding neuroblastoma, glioma, astrocytoma, osteosarcoma, meningioma,soft tissue sarcoma; haemangioma and endocrine tumours, includingpituitary adenoma, chromocytoma, paraganglioma, haematological tumourdisorders including lymphoma and leukaemias; or metastases of one of thetumours mentioned above.

The invention relates to pharmaceutical preparations comprising at leastone compound of the formula I or II and also a pharmaceuticallyacceptable carrier.

To the use of the compounds of the formula I or II as medicaments, theyare brought into the form of a pharmaceutical preparation which, inaddition to the active compound, comprises pharmaceutical organic orinorganic inert carrier materials suitable for enteral or parenteraladministration, such as, for example, water, gelatine, gum Arabic,lactose, starch, magnesium stearate, talcum, vegetable oils,polyalkylene glycols, etc.

The invention relates to a kit comprising at least one compound of theformula I, II, III, IV or V.

The term “aryl” used herein on its own or as part of another group,refers to mono- or bicyclic aromatic groups which may contain 6 to 10carbon atoms in the ring, such as, for example, phenyl or naphthyl, andin which they may have any substitution.

The aryl groups may be substituted in any suitable position leading to astable compound, by one or more radicals from the group consisting of:hydroxyl, halogen, C₁-C₅-alkyl, C₁-C₅-alkoxy, cyano, CF₃, and nitro.

Substituents which may be mentioned are methoxy, ethoxy, propoxy,isopropoxy, hydroxyl, fluorine, chlorine, bromine, methyl, ethyl,propyl, isopropyl or trifluoromethyl groups.

In each case, halogen is to be understood as meaning fluorine, chlorine,bromine or iodine.

The term “alkyl”, used herein on its own or as part of another group,refers to saturated carbon chains which may be straight-chain orbranched, in particular to methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or3-methylbutyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl groups.

C₁-C₁₀-alkyl is optionally interrupted by one or more O, S or N

The alkenyl substituents are in each case straight-chain or branched,including, for example, the following radicals: vinyl, propen-1-yl,propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl,2-methylprop-2-en-1-yl, 2-methylprop-1-en-1-yl, but-1-en-3-yl,but-3-en-1-yl; allyl.

The alkynyl groups can be straight-chain or branched and are, forexample, ethynyl, —CH₂—C≡CH, —CH₂—C≡CH, —C≡C—CH₃, —CH(CH₃)—C≡CH,—C≡C—CH₂(CH₃), —C(CH₃)₂C≡CH, —C≡C—CH(CH₃)₂—, —CH(CH₃)—C≡C—CH₃,—CH₂—C≡C—CH₂(CH₃).

Halogen represents fluoro, chloro, bromo and iodo. Preference is givento chloro, bromo and iodo.

The C₁-C₅-alkoxy groups can be straight-chain or branched and mayrepresent a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or3-methylbutoxy group.

The heteroaryl radical comprises in each case 5-10 ring atoms and may,instead of a carbon atom, contain one or more identical or differentheteroatoms, such as oxygen, nitrogen or sulphur, in the ring, and mayadditionally in each case be benzo-fused.

Examples which may be mentioned are: thienyl, furanyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, etc. pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, etc.

EXAMPLES Example 1 (2S,4S)-2-Amino-4-(3-fluoropropyl)pentanedioic acid

-   -   a) Dimethyl        (2S,4S)-4-allyl-2-tert-butoxycarbonylaminopentanedioate

11.01 g (40 mmol) of dimethyl Boc-glutamate (Advanced Chemtech) weredissolved in 160 ml of tetrahydrofuran and cooled to −70° C. 88 ml (88mmol) of a 1M solution of lithium bis(trimethylsilyl)amide intetrahydrofuran were added dropwise at this temperature over a period ofone hour, and the mixture was stirred at −70° C. for another 2 hours.14.52 g (120 mmol) of allylbromide were then added dropwise, and after 2h at this temperature, the cooling bath was removed and 200 ml of 2Naqueous hydrochloric acid and 400 ml of ethyl acetate were added. Theorganic phase was separated off, washed with water until neutral, driedover sodium sulphate and filtered, and the filtrate was concentrated.The crude product obtained in this manner was chromatographed in silicagel using a hexane/ethyl acetate gradient, and the appropriate fractionswere combined and concentrated.

Yield: 3.3 g (26.2%)

MS (ESipos): m/z 316 [M+H]+

1H-NMR (400 MHz, CHLOROFORM-d): Shift [ppm]=1.44 (s, 9H), 1.99-2.02 (m,2H), 2.31-2.39 (m, 2H), 2.56-2.61 (m, 1H), 3.67 (s, 3H), 3.73 (s, 3H),4.33-4.15 (m, 1H), 4.33-4.37 (m, 1H), 4.95-4.97 (m, 1H), 5.04-5.10 (m,2H), 5.67-5.76 (m, 1H).

b) Dimethyl(2S,4S)-2-tert-butoxycarbonylamino-4-(3-hydroxypropyl)pentanedioate

3.15 g (10 mmol) of the compound described in Example 1a were dissolvedin 50 ml of tetrahydrofuran and cooled in an ice-bath. Over a period ofabout 20 minutes, 13.3 ml of 1 M diboran/tetrahydrofuran complex intetrahydrofuran were added dropwise with ice-cooling and under nitrogen,and the mixture was stirred on ice for 1 h and at room temperatureovernight. 15 ml of 1 N aqueous sodium hydroxide solution and 13.3 ml of30% strength aqueous hydrogen peroxide solution were then addeddropwise. After 30 minutes, the mixture was diluted with water, thetetrahydrofuran was distilled off and the remaining aqueous solution wasextracted with ethyl acetate. The organic phase was separated off,washed with water until neutral, dried over sodium sulphate andfiltered, and the filtrate was concentrated. The crude product obtainedin this manner was chromatographed on silica gel using a hexane/ethylacetate gradient, and the appropriate fractions were combined andconcentrated.

Yield: 0.6 g (18%)

MS (ESipos): m/z=334 [M+H]+

1H-NMR (600 MHz, CHLOROFORM-d): Shift [ppm]=1.44 (s, 91-1), 1.47-1.98(m, 6H), 2.51-2.55 (m, 1H), 3.61-3.62 (m, 2H), 3.68 (s, 3H), 3.74 (s,3H), 4.37-4.41 (m, 1H), 5.04 (d, 1H).

c) Dimethyl(2S,4S)-2-tert-butoxycarbonylamino-4-(3-methanesulphonyloxypropyl)pentanedioate

0.17 g (0.5 mmol) of the hydroxyl compound described in Example 1b wasdissolved in dichloromethane and cooled in an ice-bath. After additionof 0.30 g (3 mmol) of triethylamine and 115 mg (1 mmol) ofmethanesulphonyl chloride, the mixture was stirred on ice for 2 h andthen concentrated. The crude product obtained in this manner waschromatographed on silica gel using a hexane/ethyl acetate gradient andthe appropriate fractions were combined and concentrated.

Yield: 145 mg (70.5%)

MS (ESIpos): m/z=412 [M+H]+

1H-NMR (300 MHz, CHLOROFORM-d): Shift [ppm]=1.44 (s, 9H), 1.68-1.79 (m,4H), 1.98-2.05 (m, 2H), 2.48-2.56 (m, 1H), 3.02 (s, 3H), 3.69 (s, 3H),3.74 (s, 3H), 4.20-424 (m, 2H), 4.30-4.39 (m, 1H), 4.95-4.99 (m, 1H).

d) Dimethyl(2S,4S)-2-tert-butoxycarbonylamino-4-(3-fluoropropyl)pentanedioate

0.33 g (1 mmol) of the hydroxyl compound described in Example 1b wasdissolved in 15 ml of dichloromethane and cooled on ice. After additionof 0.32 g (2 mmol) of diethylaminosulphur trifluoride (DAST), themixture was stirred on ice for 1 h and then washed with water, theorganic phase was dried over sodium sulphate and filtered and thefiltrate was concentrated. The crude product obtained in this manner waschromatographed on silica gel using a dichloromethane/ethyl acetategradient, and the appropriate fractions were combined and concentrated.

Yield: 25 mg (7.5%)

Elemental Analysis:

calc. C, 53.72; H, 7.81; F, 5.66; N, 4.18

found C, 53.55; H, 7.94; F 5.21; N, 4.37

e) (2S,4S)-2-Amino-4-(3-fluoropropyl)pentanedioic acid

23.5 mg (0.07 mmol) of the compound described in Example 1d weredissolved in 2 ml of tetrahydrofuran, 1 ml of 1N aqueous sodiumhydroxide solution was added and the mixture was stirred at roomtemperature for 4 h. The mixture was then concentrated to dryness, andthe resulting crude product was dissolved in about 20 ml of 3N hydrogenchloride in diethyl ether, stirred overnight, concentrated andrepeatedly coevaporated with diethyl ether. The crude product obtainedin this manner was chromatographed on C18 silica gel using awater/methanol gradient, and the appropriate fractions were combined andconcentrated.

Yield: 4 mg (27%)

Elemental Analysis (Calculated on the Anhydrous Compound):

calc. C, 46.37; H, 6.81; F, 9.17; N, 6.76

found C 46.11; H, 7.02; F, 8.87; N, 6.93

f) Dimethyl(2S,4S)-2-tert-butoxycarbonylamino-4-(3-[F-18]fluoropropyl)pentanedioate

[F-18]-Fluoride was prepared by the [O-18](p,n)[F-18] reaction in acyclotron. The isotope solution (4 GBq) was applied to a Sep-Pack LightQMA cartridge. The [F-18]-fluoride was eluted from the cartridge using aKryptofix 2.2.2/potassium carbonate solution (5 mg K2.2.2, 1 mgpotassium carbonate, acetonitrile (1.5 ml), water (0.5 ml). The solventwas removed at 120° C. in a stream of nitrogen with addition ofacetonitrile (three times 1 ml). 5 mg (12.2 μmol) of dimethyl(2S,4S)-2-tert-butoxycarbonylamino-4-(3-methane-sulphonyloxypropyl)pentanedioate1c in 1 ml of acetonitrile were added, and the resulting mixture wasstirred at 110° C. for 10 min. After cooling to about 60° C., themixture was passed through a Silica-Plus cartridge.

The intermediate was purified by HPLC (C18, acetonitrile/water. The HPLCfraction was diluted with water (about 50 ml) and passed through a C18cartridge. The intermediate was eluted with 1 ml of acetonitrile. 940MBq (39% d.c.) of dimethyl(2S,4S)-2-tert-butoxy-carbonylamino-4-(3-[F-18]fluoropropyl)pentanedioateIf were obtained in a synthesis time of 80 min.

-   -   g) (2S,4S)-2-Amino-4-(3-[F-18]fluoropropyl)pentanedioic acid

0.5 nil of 4N aqueous hydrochloric acid was added to 940 MBq of dimethyl2-tert-butoxycarbonylamino-4-(3-[F-18]fluoropropyl)pentanedioate If in 1ml of acetonitrile. With stirring, the mixture was heated at 130° C.(oil bath temperature) for 10 min. After cooling to room temperature,the solution was neutralized by addition of about 650 μl of 2N aqueoussodium hydroxide solution.

This gave 890 MBq (95% d.c.) of(2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid 1g.

Example 2 (2S,4S)-2-Amino-4-(4-fluorobutyl)pentanedioic acid a) Dimethyl(2S,4S)-2-tert-butoxycarbonylamino-4-(4-iodobutyl)pentanedioate

5.51 g (20 mmol) of dimethyl Boc-glutamate were dissolved in 60 ml oftetrahydrofuran and cooled to −70° C. Over a period of one hour, 44 ml(44 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide intetrahydrofuran were added dropwise at this temperature, and the mixturewas stirred at −70° C. for 2 hours. 18.60 g (60 mmol) of1,4-diiodobutane were then added dropwise, and after 2 h at thistemperature the cooling bath is removed and 100 ml of 2N hydrochloricacid and 300 ml of ethyl acetate were added. The organic phase wasseparated off, washed with water until neutral, dried over sodiumsulphate and filtered, and the filtrate was concentrated. The crudeproduct obtained in this manner was chromatographed on silica gel usinga hexane/ethyl acetate gradient, and the appropriate fractions werecombined and concentrated.

Yield: 1.0 g (11.0%)

Elemental Analysis:

calc. C 42.02; H, 6.17; I, 27.75; N, 3.06

found C 41.78; H, 6.30; I, 27.19; N, 3.22

b) (2S,4S)-2-Amino-4-(4-fluorobutyl)pentanedioic acid

A solution of 152 mg (1.12 mmol) of silver fluoride in 1.5 ml of waterwas added to 0.45 g (1 mmol) of the compound described in Example 2a in30 ml of acetonitrile, and the mixture was stirred at 40° C. overnight.The resulting suspension was filtered, the solution was evaporated todryness and the crude product obtained in this manner waschromatographed on silica gel using a hexane/ethyl acetate gradient, andthe appropriate fractions were combined and concentrated. The residuewas dissolved in 20 ml of tetrahydrofuran, 10 ml of 1N aqueous sodiumhydroxide solution were added and the mixture was stirred at roomtemperature for 4 h. The mixture was then concentrated to dryness, andthe resulting crude product was dissolved in about 70 ml of 3N hydrogenchloride in diethyl ether, stirred overnight, concentrated andrepeatedly coevaporated with diethyl ether. The resulting(2S,4S)-2-amino-4-(4-fluorobutyl)pentanedioic acid was chromatographedon C18 silica gel using a water/methanol gradient, and the appropriatefractions were combined and concentrated.

Yield: 33 mg (15%)

Elemental Analysis (Calculated on the Anhydrous Compound):

calc. C, 48.86; H, 7.29; F, 8.59; N, 6.33

found C, 48.66; H, 7.55; F, 8.20; N, 6.57

c) Dimethyl(2S,4S)-2-tert-butoxycarbonylamino-4-(4-[F-18]fluorobutyl)pentanedioate

[F-18]-Fluoride was prepared by the [0-18](p,n)[F-18] reaction in acyclotron. The isotope solution (5.2 GBq) was applied to a Sep-PackLight QMA cartridge. The [F-18]-fluoride was eluted from the cartridgeusing a Kryptofix 2.2.2/potassium carbonate solution (5 mg K2.2.2, 1 mgpotassium carbonate, acetonitrile (1.5 ml), water (0.5 ml). The solventwas removed at 120° C. in a stream of nitrogen with addition ofacetonitrile (three times 1 ml). 5 mg (10.9 μmol) of dimethyl(2S,4S)-2-tert-butoxycarbonylamino-4-(4-iodobutyl)pentanedioate 2a in 1ml of acetonitrile were added, and the resulting mixture was stirred at110° C. for 10 min. After cooling to about 60° C., the mixture waspassed through a silica-plus cartridge.

The intermediate was purified by HPLC(C18, acetonitrile/water). The HPLCfraction was diluted with water (about 50 ml) and passed through a C18cartridge. The intermediate was eluted with 1 ml of acetonitrile. 1.8GBq (59% d.c.) of dimethyl(2S,4S)-2-tert-butoxycarbonylamino-4-(4-[F-18]fluorobutyl)pentanedioate2c were obtained in a synthesis time of 85 min.

d) (2S,4S)-2-Amino-4-(4-[F-18]fluorobutyl)pentanedioic acid

0.5 ml of 4N aqueous hydrochloric acid was added to 1.8 GBq of dimethyl2(2S,4S)-2-tert-butoxycarbonylamino-4-(4-[F-18]fluorobutyl)pentanedioate2c in 1 ml of acetonitrile. With stirring, the mixture was heated at130° C. (oil bath temperature) for 10 min. After cooling to roomtemperature, the solution was neutralized by addition of about 700 μl of2N aqueous sodium hydroxide solution.

This gave 1.7 GBq (94% d.c.) of(2S,4S)-2-amino-4-(4-[F-18]fluorobutyl)pentanedioic acid 2d.

Example 3 (2S,4S)-2-Amino-4-(2-fluoroethoxy)pentanedioic acid a)1-tert-Butyl 2-methyl (2S,4S)-4-(2-bromoethoxy)pyrrolidine-1,2-dioate(precursor of 2-amino-4-(6-fluorohexyloxy)pentanedioic acid)

0.98 g (4 mmol) of 1-tert-butyl 2-methyl(2S,4S)-4-hydroxypyrrolidine-1,2-dioate (ALDRICH) was dissolved in 36 mlof 1,2-dibromoethane and cooled in an ice-bath. After addition of 1.36 g(4 mmol) of tetrabutylammonium bisulphite, 18 ml of 50% strength aqueoussodium hydroxide solution are added, and the mixture is stirred on icefor 2 hours and at room temperature overnight. After addition of 200 mlof water and 200 ml of dichloro-methane, the organic phase was washedonce more with water, dried over sodium sulphate and filtered, and thefiltrate was concentrated. The resulting crude product ischromatographed on silica gel using a dichloromethane/ethyl acetategradient, and the appropriate fractions are combined and concentrated.Yield: 60 mg (4.3%)

Elemental Analysis:

calc. C, 44.33; H, 6.30; Br, 22.69; N, 3.98

found C, 44.02; H, 6.33; Br, 22.21; N, 4.11

b) 1-tert-Butyl 2-methyl(2S,4S)-4-(2-bromoethoxy-5-oxopyrrolidine-1,2-dioate

106 mg (0.3 mmol) of the compound described in Example 3a were dissolvedin 10 ml of ethyl acetate. After addition of 14 mg (0.06 mmol) ofruthenium(III) chloride hydrate, a solution of 0.32 g (1.5 mmol) ofsodium periodate in 4 ml of water was added, the mixture was stirredovernight and diluted with ethyl acetate, the organic phase was washedwith water, dried over sodium sulphate and filtered and the filtrate wasconcentrated. The crude product obtained in this manner waschromatographed on silica gel using a hexane/ethyl acetate gradient, andthe appropriate fractions were combined and concentrated.

Yield: 48 mg (43.7%)

Elemental Analysis:

calc. C, 42.64; H, 5.50; Br, 21.82; N, 3.82

found C, 42.33; H, 5.74; Br, 21.17; N, 3.59

c) 1-tent-Butyl 2-methyl(2S,4S)-4-(2-fluoroethoxy)-5-oxopyrrolidine-1,2-dioate

188 mg (0.5 mmol) of Kryptofix 222 and 29 mg (0.5 mmol) of potassiumfluoride were added to 183 mg (0.5 mmol) of the compound described inExample 3b in 20 ml of dimethyl sulphoxide, and the mixture was reactedin a microwave oven at 100° C. for 30 minutes. The solution wasconcentrated under reduced pressure, the residue was partitioned betweenwater and ethyl acetate, the ethyl acetate phase was washed with water,dried over sodium sulphate and filtered and the filtrate wasconcentrated. The crude product obtained in this manner waschromatographed on silica gel using a hexane/ethyl acetate gradient, andthe appropriate fractions were combined and concentrated.

Yield: 13.7 mg (9.0%)

Elemental Analysis:

calc. C, 51.14; H, 6.60; F, 6.22; N, 4.59

d) (2S,4S)-2-Amino-4-(2-fluoroethoxy)pentanedioic acid

21.4 mg (0.07 mmol) of the compound described in Example 3c weredissolved in 2 ml of tetrahydrofuran, 1 ml of 1N aqueous sodiumhydroxide solution was added and the mixture was stirred at roomtemperature for 4 h. The mixture is then evaporated to dryness, and theresulting crude product is suspended in about 20 ml of 6N aqueoushydrochloric acid, stirred at 80° C. for 6 h and concentrated. The crudeproduct obtained in this manner was chromatographed on C18 silica gelusing a water/methanol gradient, and the appropriate fractions werecombined and concentrated.

Yield: 3.2 mg (22%)

Elemental Analysis (Calculated on the Anhydrous Compound):

calc.: C, 40.19; H, 5.78; F, 9.08; N, 6.70

found: C, 39.82; H, 5.86; F, 8.81; N, 6.96

e) 1-tert-Butyl 2-methyl(2S,4S)-4-(24F-181-fluoroethoxy)-5-oxopyrrolidine-1,2-dioate

[F-18]-Fluoride was prepared by the [0-18](p,n)[F-18] reaction in acyclotron. The isotope solution (3.9 GBq) was applied to a Sep-PackLight QMA cartridge. The [F-18]-fluoride was eluted from the cartridgeusing a Kryptofix 2.2.2/potassium carbonate solution (5 mg K2.2.2, 1 mgpotassium carbonate, acetonitrile (1.5 ml), water (0.5 ml). The solventwas removed at 120° C. in a stream of nitrogen with addition ofacetonitrile (three times 1 ml).

5 mg (13.7 μmol) of 1-tert-butyl 2-methyl(2S,4S)-4-(2-bromoethoxy)pyrrolidine-1,2-dioate 3a in 1 ml ofacetonitrile were added, and the resulting mixture was stirred at 100°C. for 10 min. After cooling to about 70° C., the mixture was passedthrough a silica-plus cartridge. The intermediate was purified by HPLC(C18, acetonitrile/water). The HPLC fraction was diluted with water(about 50 ml) and passed through a C18 cartridge. The intermediate waseluted with 1 ml of acetonitrile. 1.3 GBq (52% d.c.) of 1-tert-butyl2-methyl (2S,4S)-4-(2-[F-18]fluoroethoxy)-5-oxopyrrolidine-1,2-dioate 3ewere obtained in a synthesis time of 70 min.

f) (2S,4S)-2-Amino-4-(2-[F-18]fluoroethoxy)pentanedioic acid

0.5 ml of 4N aqueous hydrochloric acid was added to 1.3 GBq of1-tert-butyl 2-methyl(2S,4S)-4-(2-[F-18]difluoroethoxy)-5-oxopyrrolidine-1,2-dioate 3e in 1ml of acetonitrile. With stirring, the mixture was heated at 130° C.(oil bath temperature) for 10 min. After cooling to room temperature,the solution was neutralized by addition of about 700 μl of 2N aqueoussodium hydroxide solution.

This gave 1.2 GBq (92% d.c.) of(2S,4S)-2-amino-4-(2-fluoroethoxy)pentanedioic acid 3f.

Example 4 Cell Experiments

The uptake of the glutamic acid derivatives according to the inventioninto tumour cells was investigated in cell experiments. Here, the uptakeof a radiolabelled glutamic acid derivative (4R/S—[F-18]F-L-glutamicacid) was examined in the presence of the compounds according to theinvention and control substances (competition experiments). Thecompounds according to the invention were employed in excess (1 mM) over4R/S—[F-18]F-L-glutamic acid (tracer).

Native L-configured glutamic acid (L-Glu), which, at a concentration of1 mM L-Glu causes an 87% inhibition of tracer uptake in the assay, wasused as positive control. Surprisingly, it was found that 4S-configuredmethyl and hydroxy derivatives inhibit tracer uptake considerably betterin each case than the corresponding 4R-configured derivatives. For the4-hydroxy derivatives, competition values of 87% were determined for theS-configured derivative, whereas for the R-configured derivative, only70% competition were determined. For the 4S-methyl derivative, even 92%inhibition were found whereas for the 4R-methyl derivative only 64%inhibition were found.

4S-(3-Fluoropropyl)-L-Glu showed a considerably better inhibition thanother derivatives examined. Thus, 1 mM 4S-(3-fluoropropyl)-L-Glu wasable to reduce tracer uptake by >94% to 5.4%.

TABLE 1 Examination of the biological activity of compounds according tothe invention in the competition cell experiment. (A549 cells, 10 min ofincubation with 0.250 MBq of 4R/S-[F-18]F-L-Glu in PBS buffer,competitor concentration 1 mM) (FIG. 1) % Tracer uptake S.D. Control100.0 3.5 L-Glu 12.6 1.6 (4R/S)-fluoro-D/L-Glu 16.3 2.5(4S)-hydroxy-L-Glu 13.2 1.8 (4R)-hydroxy-L-Glu 29.6 4.2(4S)-methyl-L-Glu 7.7 1.9 (4R)-methyl-L-Glu 33.5 5.54S-(3-fluoropropyl)-L-Glu 5.4 2.2

Cell Uptake of S-Configured, F-18-Labelled Glutamic Acid Derivatives

Following labelling with F-18,(2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid was examinedin cell experiments with A549 and H460 tumour cells (both humannon-small-cell bronchial carcinoma cell lines). Here, a time-dependentcellular uptake was observed. After 30 min of incubation, it waspossible to measure an uptake of 899 000 cpm per 100 000 cells for(2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid. Accordingly,(2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid accumulates toa greater degree in these tumour cells than the “Gold standard”[F-18]FDG after 30 minutes of incubation.

FIG. 2: time-dependent cellular uptake of(2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid compared to[F-18]FDG. For all F-18-labelled compounds, a time-dependentintracellular radioactivity was observed. After 30 min, 840 000 cpm/100000 cells of (2S,4S)-2-amino-4(3-[F-18]fluoropropyl)pentanedioic acidhad been taken up. In the case of [F-18]FDG, 770 000 cpm/100 000 cellshad been taken up after 30 min.

Animal Experiments

(2S,4S)-2-Amino-4-(3-[F-18]fluoropropyl)pentanedioic acid was studied inmice bearing A549 tumours in an organ distribution experiment. (Table 2)

0.25 h after injection, 2.4% of the injected dose per g (% ID/g) wasmeasured in the tumour, after 1 h, the tumour uptake is 1.6% ID/g. Atransient uptake or excretions were observed in the kidneys and thepancreas. Thus, after 0.25 h, an uptake of 14.4% ID/g and 13.6% ID/g,respectively, was observed in these organs. After 1 h, the activity inthese organs was reduced to 2% 1D/g and 4% ID/g, respectively.

At all points in time, the uptake into the bones was <0.5% 1D/g.

TABLE 2 Organ distribution after i.v. administration of 250 kBq of(2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid (F-18 FSPG) inmice bearing A549 tumours. Time 0.25 h 0.5 h 1.0 h 2.00 h % dose/g S.D.S.D. S.D. S.D. spleen 2.87 0.11 1.76 0.38 1.02 0.07 0.53 0.13 liver 0.550.11 0.46 0.12 0.21 0.03 0.11 0.03 kidney 14.38 4.41 6.44 0.71 2.01 0.170.80 0.17 lung 1.35 0.03 1.08 0.19 0.50 0.08 0.29 0.02 bone 0.44 0.060.37 0.07 0.20 0.03 0.20 0.03 heart 0.42 0.08 0.20 0.02 0.08 0.01 0.050.00 brain 0.09 0.01 0.10 0.05 0.06 0.01 0.05 0.01 fat 0.31 0.30 0.080.03 0.04 0.01 0.09 0.11 thyroid 1.17 0.33 1.31 0.55 0.77 0.24 0.42 0.10muscle 0.17 0.03 0.09 0.00 0.05 0.00 0.03 0.00 tumour 2.42 0.39 1.820.21 1.58 0.15 0.97 0.21 skin 1.71 0.20 2.26 0.64 1.80 0.04 1.01 0.10blood 0.72 0.12 0.35 0.06 0.13 0.01 0.07 0.01 tail 2.74 0.34 3.45 1.861.19 0.13 1.69 0.60 stomach 3.25 0.27 2.64 0.70 0.96 0.29 0.39 0.09ovary 1.82 0.29 1.13 0.48 0.94 0.56 0.28 0.20 uterus 1.30 0.47 1.27 0.740.93 0.44 0.37 0.33 intestine 1.27 0.06 0.90 0.28 0.52 0.06 0.32 0.07pancreas 13.64 0.59 8.51 0.65 3.99 0.66 1.35 0.15 adrenals 0.94 0.230.78 0.38 0.27 0.11 0.20 0.04PET/CT Imaging with (2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioicAcid in Mice Bearing A549 Tumours

60 min after i.v. administration of 10 MBq of(2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid to micecarrying A549 tumours, a 20 min data acquisition using a PET/CT scanner(Inveon) was started. Image analysis shows a high uptake of(2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid into the A549tumour.

PET with (4S)-4-(3-[F-18]fluoropropyl)-L-Glu with Rats Bearing H460Tumours

80 min after i.v. administration of 18 MBq of(2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid in ratsbearing H460 tumours, a 20 min data acquisition with a PET scanner(Inveon) was started. Image analysis shows a high uptake of(2S,4S)-2-amino-4-(3-[4F-18]fluoropropyl)pentanedioic acid into the H460tumour.

FIG. 3. PET/CT study with(2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid in micebearing A549 tumours (to the left, section image analyses, to the right,maximum intensity projection, 90 min. after i.v. administration of 10MBq (4S)-4-(34F-181-fluoropropyl)-L-Glu)

FIG. 4. PET with (2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioicacid in rats bearing H460 tumours (section image analysis, 0.80-100 minafter i.v. administration of 16 MBq of(4S)-4-(3-[F-18]fluoropropyl)-L-Glu)

FIG. 5. PET with (2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioicacid in rats bearing H460 tumours (maximum intensity projection, 80-100min after i.v. administration of 16 MBq of(2S,4S)-2-amino-4-(3-[F-18]fluoropropyl)pentanedioic acid.

Example 5 (2S,4S)-2-Amino-4-(3-[F-18]fluoropropyl)-pentanedioate a)di-tert-butyl (2S,4S)-4-allyl-2-tert-butoxycarbonylamino-pentanedioate

26.96 g (75 mmol) of di-tert-butyl Boc-glutamate (Journal of PeptideResearch (2001), 58, 338) were dissolved in 220 mL of tetrahydrofuran(THF) and cooled to −70° C. 165 mL (165 mmol) of a 1M solution oflithium bis(trimethylsilyl)amide in THF were added dropwise over aperiod of two hours at this temperature and the mixture was stirred at−70° C. for another 2 hours. 27.22 g (225 mmol) of allyl bromide werethen added dropwise, and after 2 h at this temperature, the cooling bathwas removed and 375 mL of 2N aqueous hydrochloric acid and 1.25 L ofethyl acetate were added. The organic phase was separated off, washedwith water until neutral, dried over sodium sulphate and filtered, andthe filtrate was concentrated. The crude product obtained in this mannerwas chromatographed in silica gel using a hexane/ethyl acetate gradient,and the appropriate fractions were combined and concentrated.

Yield: 15.9 g (53.1%)

MS (ESIpos): m/z=400 [M+H]⁺

1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.32-1.58 (m, 274-1) 1.81-1.92 (m,2H) 2.25-2.39 (m, 2H) 2.40-2.48 (m, 1H), 4.10-4.18 (m, 1H) 4.85-4.92 (d,1H) 5.02-5.11 (m, 2H) 5.68-5.77 (m, 1H)

b) di-tert-butyl(2S,4S)-2-tert-butoxycarbonylamino-4-(3-hydroxypropyl)-pentanedioate

15.58 g (39 mmol) of di-led-butyl(2S,4S)-4-allyl-2-tert-butoxycarbonylamino-pentanedioate 5a weredissolved in 200 mL of tetrahydrofuran (THF) and cooled in an ice-bath.Over a period of about 20 minutes, 54.6 mL (54.6 mmol) of 1 Mdiboran/tetrahydrofuran complex in tetrahydrofuran were added dropwisewith ice-cooling and under nitrogen, and the mixture was stirred on icefor 2 h and at room temperature overnight. It was cooled again to 0° C.and 58.5 mL of 1 N aqueous sodium hydroxide solution and 58.5 mL of 30%aqueous hydrogen peroxide solution were then added dropwise. After 60minutes, the mixture was diluted with water, the tetrahydrofuran wasdistilled off and the remaining aqueous solution was extracted withethyl acetate. The organic phase was separated off, washed with wateruntil neutral, dried over sodium sulphate and filtered, and the filtratewas concentrated. The crude product obtained in this manner waschromatographed on silica gel using a hexane/ethyl acetate gradient, andthe appropriate fractions were combined and concentrated.

Yield: 8.5 g (52.2%)

MS (ESIpos): m/z=418 [M+H]⁺

1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.32-1.58 (m, 27H) 1.60-1.70 (m,2H) 1.73-1.94 (m, 4H) 2.05-2.12 (m, 1H), 2.33-2.40 (m, 1H) 3.58-3.68 (m,2H) 4.15-4.22 (m, 1H) 4.95-5.03 (d, 1H)

c) di-tert-butyl(2S,4S)-2-tert-butoxycarbonylamino-4-(3-nitrophenylsulfonyloxy-propyl)pentanedioate

5.22 g (12.5 mmol) of di-tert-butyl(2S,4S)-2-tert-butoxycarbonylamino-4-(3-hydroxypropyl)pentanedioate 5bwere dissolved in 125 mL of dichloromethane and cooled in an ice-bath.After addition of 7.59 g (75 mmol) of triethylamine and 5.54 g (25 mmol)nitrophenylsulphonyl chloride, the mixture was stirred on ice for 2 hand then concentrated. The crude product obtained in this manner waschromatographed on silica gel using a hexane/ethyl acetate gradient andthe appropriate fractions were combined and concentrated.

Yield: 4.7 g (62.4%)

MS (ESIpos): m/z=603 [M+H]⁺

1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.42-1.45 (m, 27H) 1.57-1.87 (m,6H) 2.29 (m, 1H) 4.01 (m, 1H) 4.13-4.16 (m, 2H) 4.86 (d, 1H) 8.12 (d,2H) 8.42 (d, 2H)

d) di-tert-butyl(2S,4S)-2-tert-butoxycarbonylamino-4-(3-fluoropropyl)-pentanedioate

29.22 g (70 mmol) of the hydroxyl compound described in Example 5b weredissolved in 700 mL of tetrahydrofuran (THF) and then 42.5 g (420 mmol)triethylamine was added. After addition of 25.14 g (140 mmol) ofperfluorbutanefluoride acid (Aldrich) and 22.57 g (140 mmol)triethylamine/fluorohydroxyde (Aldrich), the mixture was stirred at roomtemperature 65 h, was concentrated and the crude product obtained inthis manner was chromatographed in silica gel using a hexane/ethylacetate gradient, and the appropriate fractions were purified andconcentrated.

Yield: 15.9 g (54.1%)

MS (ESIpos): m/z=420 [M+H]⁺

1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.40-1.55 (m, 27H) 1.60-1.95 (m,6H) 2.33-2.42 (m, 1H) 4.15-4.22 (m, 1H) 4.30-4.40 (m, 1H) 4.48-4.55 (m,1H) 4.85-4.90 (d, 1H)

e) (2S,4S)-2-Amino-4-(3-fluoropropyl)-pentanedioate

15.52 g (37 mmol) of the example 5d were dissolved gently in 110 mLTrifluoroacid and 3 days at room temperature stirred. The mixture wasconcentrated by drying and the crude product obtained in this manner wasdistilled 0.3 times with Diethylether and the rest was dissolved inaround 200 mL water, with 20 mL 1N Salzsäure of pH 2, and washed withDichloromethane and Ethylacetate subsequently and the solution wasplaced at a pH 7.4, with a 1 N sodium salt (ca. 65 mL) auf pH 7.4, thesolution was dry-frozen and then was chromatographed in silica gel usinga hexane/ethyl acetate gradient, and the appropriate fractions werepurified and concentrated.

Yield: 7.5 g (88%)

MS (ESIpos): m/z=208 [M+H]⁺

1H NMR (300 MHz, methanol-d) d ppm 1.62-1.87 (m, 5H) 2.11 (m, 1H)2.47-2.52 (m, 1H) 3.45 (m, 1H) 4.41 (m, 2H)

f) di-tert-butyl(2S,4S)-2-tert-Butoxycarbonylamino-4-(3-[F-18]fluoropropyl)pentanedioate

[F-18]-Fluoride was prepared by the [O-18](p,n)[F-18] reaction in acyclotron. The isotope solution (3.5 GBq) was applied to a Sep-PackLight QMA cartridge. The [F-18]-fluoride was eluted from the cartridgeusing a Kryptofix 2.2.2/potassium carbonate solution (5 mg K2.2.2, 1 mgpotassium carbonate, acetonitrile (1.5 ml), water (0.5 ml). The solventwas removed at 120° C. in a stream of nitrogen with addition ofacetonitrile (three times 1 ml).

5 mg (8.3 μmol) di-tort-butyl ester(2S,4S)-2-tert-Butoxycarbonylamino-4-(3-[4-Nitrobenzenesulfonyloxy-propyl)-pentanedioate5c in 1 mL Acetonitrile were added, and the resulting mixture wasstirred at 110° C. for 10 min. After cooling to about 60° C., themixture was passed through a silica-plus cartridge.

The intermediate was purified by HPLC(C18, acetonitrile/water). The HPLCfraction was diluted with water (about 50 ml) and passed through a C18cartridge. The intermediate was eluted with 1 ml of acetonitrile. 970MBq (46% d.c.) of di-t-butyl ester(2S,4S)-2-tert-Butoxycarbonylamino-4-(3-[F-18]fluoropropyl)-pentanedioate5f were obtained in a synthesis time of 80 min.

h) (2S,4S)-2-Amino-4-(3-[F-18]fluoropropyl)-pentanedioate

960 MBq of di-tort-butyl(2S,4S)-2-tert-Butoxycarbonylamino-4-(3-[F-18]fluoropropyl)pentanedioate5f in 1 mL Acetonitrile were with 0.5 mL 4N HCl versetzt. The mixturewas stirred 10 min at the heated temperature of 130° C. (oil bathtemperature). After cooling to room temperature, the solution wasneutralised with the addition of around 650 μL 2N NaOH.

This gave 920 MBq (97% d.c.) of(2S,4S)-2-amino-4-(3-fluoropropyl)pentanedioate.

Beispiel 6 di-tert-butyl(2S,4S)-2-tent-Butoxycarbonylamino-4-(3-p-toluolsulfonyloxy-propyl)pentanediote

418 mg (1 mmol) of di-tert-butyl(2S,4S)-2-tert-butoxycarbonylamino-4-(3-hydroxypropyl)pentanedioate 5bwere dissolved in 20 mL of dichloromethane and cooled in an ice-bath.After addition of 0.61 g (6 mmol) of triethylamine and 0.38 g (2 mmol)p-toluenesulphonyl chloride, the mixture was stirred on ice for 2 h,overnight at room temperature and then concentrated. The crude productobtained in this manner was chromatographed on silica gel using ahexane/ethyl acetate gradient and the appropriate fractions werecombined and concentrated.

Yield: 0.37 g (64.7%)

MS (ESIpos): m/z=572 [M+H]⁺

1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.37-1.93 (m, 33H) 2.18-2.35 (m,4H) 4.01-4.16 (m, 3H) 4.84 (d, 1H) 7.35 (d, 2H) 7.78 (d, 2H)

b) di-tert-butyl(2S,4S)-2-tert-Butoxycarbonylamino-4-(3-[F-18]difluoropropyl)pentanedioate

[F-18]-Fluoride was prepared by the [0-18](p,n)[F-18] reaction in acyclotron. The isotope solution (5.2 GBq) was applied to a Sep-PackLight QMA cartridge. The [F-18]-fluoride was eluted from the cartridgeusing a Kryptofix 2.2.2/potassium carbonate solution (5 mg K2.2.2, 1 mgpotassium carbonate, acetonitrile (1.5 ml), water (0.5 ml). The solventwas removed at 120° C. in a stream of nitrogen with addition ofacetonitrile (three times 1 ml).

5 mg (8.7 μmol) di-tert-butyl(2S,4S)-2-tert-Butoxycarbonylamino-4-(3-[toluenesulfonyloxypropyl)-pentanedioate6a was added to in 1 mL Acetonitrile and the resulting mixture is 10 minat 110° C. stirred. After cooling to about 60° C., the mixture waspassed through a silica-plus cartridge.

The intermediate was purified by HPLC(C18, acetonitrile/water). The HPLCfraction was diluted with water (about 50 ml) and passed through a C18cartridge. The intermediate was eluted with 1 ml of acetonitrile.

920 MBq (41% d.c.) di-tert-butyl(2S,4S)-2-tert-Butoxycarbonylamino-4-(3-[F-18]fluoropropyl)-pentanedioate5f were obtained in a synthesis time of 80 min.

i) (2S,4S)-2-Amino-4-(3-[F-18]fluoropropyl)-pentanedioate

960 MBq ofdi-tert-butyl(2S,4S)-2-tert-Butoxycarbonylamino-4-(3-[F-18]fluoropropyl)pentanedioate5f in 1 mL Acetonitrile and then 0.5 mL 4N HCl was added. The mixturewas stirred 10 min at the heated temperature of 130° C. (oil bathtemperature). After cooling to room temperature, the solution wasneutralised with the addition of around 650 μL 2N NaOH

This gave 870 MBq (95% d.c.) of(2S,4S)-2-amino-4-(3-fluoropropyl)pentanedioate.

BRIEF DESCRIPTION OF DRAWINGS

FIGS. 1 and 2 are graphs.

FIGS. 3-5 are images.

FIG. 6 is a graph.

1) Compounds of the general formula I

in which A represents a) hydroxyl, b) branched or straight-chain C₁-C₅alkoxy, c) branched or straight-chain hydroxy C₁-C₅ alkoxy, d) branchedor straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄ alkyl)_(n)-O—C₁-C₄ alkyl, e)N(C₁-C₅ alkyl)₂, f) NH₂, g) N(H)-L, h) O-L or i) O—Z, G represents a)hydroxyl, b) O—Z, b) branched or straight-chain O—C₁-C₅ alkyl, c)branched or straight-chain O—C₂-C₅ alkenyl, d) branched orstraight-chain O—C₁-C₅ alkyl-(O—C₁-C₄ alkyl)_(n)-O—C₁-C₄ alkyl, e)branched or straight-chain O—C₂-C₅ alkynyl or f) triphenylmethoxy, R¹and R² represent a) hydrogen, b) branched or straight-chain alkoxy, c)branched or straight-chain ¹⁸F—C₁-C₅ alkyl, d) branched orstraight-chain ¹⁸F—C₂-C₅ alkenyl, e) branched or straight-chain¹⁸F—C₂-C₅ alkynyl, f) hydroxyl, g) branched or straight-chain C₁-C₅alkyl or h) branched or straight-chain C₁-C₅ alkoxy, alkyl beingoptionally interrupted by one or more O, S or N, with the proviso thatone of the substituents R¹ or R² contains exactly one ¹⁸F isotope andthe respective other substituent contains no ¹⁸F isotope, with theproviso that R¹ is not hydrogen, L represents a) branched orstraight-chain C₁-C₅ alkyl, b) branched or straight-chain C₂-C₅ alkenyl,c) branched or straight-chain C₁-C₅ alkyl-(O—C₁-C₄ alkyl)_(n)-O—C₁-C₄alkyl or d) branched or straight-chain C₂-C₅ alkynyl, Z represents ametal cation equivalent, and where n=0, 1, 2 or
 3. 2) Compoundsaccording to claim 1, characterized in that R¹ is selected from thegroup consisting of ¹⁸F-methoxy, ¹⁸F-ethoxy, ¹⁸F-propoxy, ¹⁸F-ethyl and¹⁸F-propyl, and R² is hydrogen. 3) Compound according to claim 1,selected from the group of compounds of the formulae:

4) Compounds of the general formula (II):

in which A′ represents a) hydroxyl, b) branched or straight-chain C₁-C₅alkoxy, c) branched or straight-chain hydroxy C₁-C₅ alkoxy, d) branchedor straight-chain O—C₁-C₅ alkyl-(O—C₁-C₄ alkyl)_(n)-O—C₁-C₄ alkyl, e)N(C₁-C₅ alkyl)₂, f) NH₂, g) N(H)-L′, h) O-L′, G′ represents a) hydroxyl,b) O—Z′, c) branched or straight-chain O—C₁-C₅ alkyl, d) branched orstraight-chain O—C₂-C₅ alkenyl, e) branched or straight-chain O—C₁-C₅alkyl-(O—C₁-C₄ alkyl)_(n)-O—C₁-C₄ alkyl, f) branched or straight-chainO—C₂-C₅ alkynyl or g) triphenylmethoxy, R¹ and R² represent a) hydrogen,b) branched or straight-chain ¹⁸F—C₁-C₅ alkoxy, c) branched orstraight-chain ¹⁸F—C₁-C₅ alkyl, d) branched or straight-chain ¹⁸F—C₂-C₅alkenyl, e) branched or straight-chain ¹⁸F—C₂-C₅ alkynyl, f) hydroxyl,g) branched or straight-chain C₁-C₅ alkyl or h) branched orstraight-chain C₁-C₅ alkoxy, alkyl being optionally interrupted by oneor more O, S or N, with the proviso that exactly one of the substituentsR¹ or R² contains exactly one ¹⁸F isotope and the respective othersubstituent contains no ¹⁸F isotope, with the proviso that R¹ is nothydrogen, Q represents a) N(H)-tert-butoxycarbonyl, b)N(H)-allyloxycarbonyl, c) N(H)-benzyloxycarbonyl, d)N(H)-ethoxycarbonyl, e) N(H)-methoxycarbonyl, f) N(H)-propoxycarbonyl,e) N(H)-2,2,2-trichloroethoxycarbonyl, f) N(H)-1,1-dimethylpropynyl, g)N(H)-1-methyl-1-phenylethoxycarbonyl, h)N(H)-1-methyl-1-(4-biphenylyl)ethoxycarbonyl, i)N(H)-cyclobutylcarbonyl, j) N(H)-1-methylcyclobutylcarbonyl, k)N(H)-vinylcarbonyl, l) N(H)-allylcarbonyl, m) N(H)-adamantylcarbonyl, n)N(H)-diphenylmethylcarbonyl, o) N(H)-cinnamylcarbonyl, p) N(H)-formyl,q) N(H)-benzoyl, r) N(H)-trityl, s) N(H)-p-methoxydiphenylmethyl, t)N(H)-di(p-methoxyphenyl)phenylmethyl,

v) N-(tert-butoxycarbonyl)₂, L′ represents a) branched or straight-chainC₁-C₅ alkyl, b) branched or straight-chain C₂-C₅ alkenyl, c) branched orstraight-chain C₁-C₅ alkyl-(O—C₁-C₄ alkyl)_(n)-O—C₁-C₄ alkyl or d)branched or straight-chain C₂-C₅ alkynyl, X′ and X″ independently of oneanother represent a) branched or straight-chain C₁-C₅ alkyl, b)substituted or unsubstituted aryl, c) substituted or unsubstitutedaralkyl or d) substituted or unsubstituted heteroaryl, Z′ represents ametal cation equivalent, and where n=0, 1, 2 or
 3. 5) Compound accordingto claim 4, characterized in that R¹ is selected from the groupconsisting of ¹⁸F-ethoxy, ¹⁸F-propoxy, ¹⁸F-ethyl, and ¹⁸F-propyl, and R²is hydrogen.
 6. Compound according to claim 4 or 5, characterized inthat Q is selected from the group consisting ofN(H)-tert-butoxycarbonyl, N(H)-benzyloxycarbonyl and

in which X′ and X″ independently of one another represent a) branched orstraight-chain C₁-C₅ alkyl, b) substituted or unsubstituted aryl, c)substituted or unsubstituted aralkyl or d) substituted or unsubstitutedheteroaryl. 7) Process for preparing compounds of the general formula(I) according to any of claims 1 to 3, which comprises removing one ormore protective groups present in a compound of the formula (II)according to any of claims 4 to
 6. 8) Process for preparing compounds ofthe general formula (II) according to any of claims 4 to 6, whichcomprises reacting a compound of the formula (III) according to claim 12with F-18 fluoride. 9) Compounds according to any of claims 1 to 6 foruse as medicaments. 10) Compounds according to any of claims 1 to 6 foruse for imaging in tumour disorders. 11) Use of compounds according toany of claims 1 to 6 for preparing a medicament for imaging in tumourdisorders. 12) Compounds of the formula (III)

in which A″ represents a) branched or straight-chain C₁-C₅ alkoxy, b)branched or straight-chain hydroxy C₁-C₅ alkoxy, c) branched orstraight-chain O—C₁-C₅ alkyl-(O—C₁-C₄ alkyl)_(n)-O—C₁-C₄ alkyl, d)N(C₁-C₅ alkyl)₂, e) NH₂, f) N(H)—U′ g) N(H)-L″, or h) O-L″, G″represents a) O—Z″, b) branched or straight-chain O—C₁-C₅ alkyl, c)branched or straight-chain O—C₂-C₅ alkenyl, d) branched orstraight-chain O—C₁-C₅ alkyl-(O—C₁-C₄ alkyl)_(n)-O—C₁-C₄ alkyl, e)branched or straight-chain O—C₂-C₅ alkynyl or f) triphenylmethoxy, R³and R⁴ represent a) hydrogen, b) branched or straight-chain E-C₁-C₅alkoxy, c) branched or straight-chain E-C₁-C₅ alkyl, d) branched orstraight-chain E-C₂-C₅ alkenyl, e) branched or straight-chain E-C₂-C₅alkynyl, f) hydroxyl, g) branched or straight-chain C₁-C₅ alkyl or h)branched or straight-chain C₁-C₅ alkoxy, alkyl being optionallyinterrupted by one or more O, S or N, with the proviso that exactly oneof the substituents R³ or R⁴ contains an E and the respective othersubstituent contains no E, with the proviso that R³ is not hydrogen, Erepresents a leaving group, Q′ represents a) N(H)-tert-butoxycarbonyl b)N(H)-allyloxycarbonyl, c) N(H)-benzyloxycarbonyl, d)N(H)-ethoxycarbonyl, e) N(H)-methoxycarbonyl, f) N(H)-propoxycarbonyl,g) N(H)-2,2,2-trichloroethoxycarbonyl, h) N(H)-1,1-dimethylpropynyl, i)N(H)-1-methyl-1-phenylethoxycarbonyl, j)N(H)-1-methyl-1-(4-biphenylyl)ethoxycarbonyl, k)N(H)-cyclobutylcarbonyl, l) N(H)-1-methylcyclobutylcarbonyl, m)N(H)-vinylcarbonyl, n) N(H)-allylcarbonyl, o) N(H)-adamantylcarbonyl, p)N(H)-diphenylmethylcarbonyl, q) N(H)-cinnamylcarbonyl, r) N(H)-formyl,s) N(H)-benzoyl, t) N(H)-trityl, u) N(H)-p-methoxydiphenylmethyl, v)N(H)-di(p-methoxyphenyl)phenylmethyl,

x) N-(tert-butoxycarbonyl)₂, L″ represents a) branched or straight-chainC₁-C₅ alkyl, b) branched or straight-chain C₂-C₅ alkenyl, c) branched orstraight-chain C₁-C₅ alkyl-(O—C₁-C₄ alkyl)_(n)-O—C₁-C₄ alkyl or d)branched or straight-chain C₂-C₅ alkynyl, X′ and X″ independently of oneanother represent a) branched or straight-chain C₁-C₅ alkyl, b)substituted or unsubstituted aryl, c) substituted or unsubstitutedalkylaryl or d) substituted or unsubstituted heteroaryl, Z″ represents ametal cation equivalent, and where n=0, 1, 2 or
 3. 13) Use of compoundsof the formula (IV) for preparing compounds of the formula (I) or (II):

in which G′″ represents a) branched or straight-chain O—C₁-C₅ alkyl, b)branched or straight-chain O—C₂-C₅ alkenyl, c) branched orstraight-chain O—C₁-C₅ alkyl-(O—C₁-C₄ alkyl)_(n)-O—C₁-C₄ alkyl, d)branched or straight-chain O—C₂-C₅ alkynyl or e) triphenylmethoxy, R⁵and R⁶ represent a) hydrogen, b) hydroxyl, c) branched or straight-chainC₁-C₅ alkyl, d) branched or straight-chain C₁-C₅ alkoxy or e) R⁷-E, withthe proviso that exactly one of the substituents R⁵ or R⁶ contains an E′and the respective other substituent contains no E′, with the provisothat R⁵ is not hydrogen, E′ represents a leaving group, R⁷ represents a)branched or straight-chain C₁-C₅ alkoxy, b) branched or straight-chainC₁-C₅ alkyl, c) branched or straight-chain C₂-C₅ alkenyl or d) branchedor straight-chain C₂-C₅ alkynyl, Q′″ represents a) N-tert-butoxycarbonylb) N-allyloxycarbonyl, c) N-benzyloxycarbonyl, d) N-ethoxycarbonyl, e)N-methoxycarbonyl, f) N-propoxycarbonyl, g)N-2,2,2-trichloroethoxycarbonyl, h) hydrogen, i)N-1-methyl-1-phenylethoxycarbonyl, j)N-1-methyl-1-(4-biphenylyl)ethoxycarbonyl, k) N-cyclobutylcarbonyl, l)N-1-methylcyclobutylcarbonyl, m) N-vinylcarbonyl, n) N-allylcarbonyl, o)N-adamantylcarbonyl, p) N-diphenylmethylcarbonyl, q) N-cinnamylcarbonyl,r) N-formyl, s) N-benzoyl, t) N(H)-trityl, u)N(H)-p-methoxyphenyldiphenylmethyl, v)N(H)-di(p-methoxyphenyl)phenylmethyl,

x) N-(tert-butoxycarbonyl)₂, X′ and X″ independently of one anotherrepresent a) branched or straight-chain C₁-C₅ alkyl, b) substituted orunsubstituted aryl, c) substituted or unsubstituted alkylaryl or d)substituted or unsubstituted heteroaryl, and where n=0, 1, 2 or
 3. 14)Imaging kit, comprising compounds of the general formula III or IV. 15)Pharmaceutical composition, comprising compounds of the general formulaI, II, III or IV and suitable pharmaceutical carrier substances. 16)Compounds according to any of claims 1 to 6, and compounds of thegeneral formula IV, characterized in that the compounds are suitable forimaging in a dosage range of 37-600 MBq. 17) Compound according to claim16, characterized in that the compounds are particularly suitable in adosage range of 150 MBq-370 MBq.